Tricyclic heterocyclic compounds and jak inhibitors

ABSTRACT

This disclosure relates to novel tricyclic pyrimidine compounds and tricyclic pyridine compounds having JAK inhibitory activities. A tricyclic heterocyclic compound represented by the formula (I b ), wherein the rings A b  and B b , X b , Y b , R 1b , R 2b , R 3b , L 1b , L 2b , L 3b  and n b  are as defined in the specification.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. Non-Provisional applicationSer. No. 14/238,507, which was filed on Feb. 12, 2014. Application Ser.No. 14/238,507 is a National Stage of PCT/JP2012/070876, which was filedon Aug. 10, 2012. This application is based upon and claims the benefitof priority to: Japanese Application No. 2011/177270, which was filed onAug. 12, 2011; Japanese Application No. 2011-177289, which was filed onAug. 12, 2011; Japanese Application No. 2012-097073, which was filed onApr. 20, 2012; Japanese Application No. 2012-103516, which was filed onApr. 27, 2012; and Japanese Application No. 2012-103517, which was filedon Apr. 27, 2012.

TECHNICAL FIELD

The present invention relates to novel tricyclic pyrimidine compoundsand tricyclic pyridine compounds having JAK inhibitory activities.

BACKGROUND ART

The JAK (Janus kinase) family is a tyrosine kinase family consisting offour members, JAK1, JAK2, JAK3 and Tyk2 (Tyrosine kinase 2) and plays animportant role in cytokine signaling.

While the kinases of this family, except for JAK3, are widely expressedin tissues, expression of JAK3 is restricted to immune cells. This isconsistent with the fact that JAK3 plays an important role in variousreceptor-mediated signaling pathways such as IL (interleukin)-2, IL-4,IL-7, IL-9, IL-15 and IL-21 signaling by noncovalently associating withthe common γ chain (Non-Patent Documents 1 and 2).

Lowered JAK3 protein levels or defects in the common γ chain geneobserved in patients with an immunodeficiency called X-linked SevereCombined Immuno Deficiency (XSCID) suggest that blocking of the JAK3signaling pathway leads to immunosuppression (Non-Patent Documents 3 and4). Animal experiments indicate the importance of JAK3 not only inmaturation of B- and T-lymphocytes but also in maintenance ofT-lymphocyte functions. Therefore, regulation of immune responses viathis mechanism is a promising therapy for T-cell lymphoproliferativediseases such as organ transplant rejection and autoimmune diseases.

Analyses of JAK1 knockout mice and JAK1-deficient cells suggestinvolvement of JAK1 in various receptor-mediated signaling pathways suchas IFN (Interferon)α, IFNβ, IFNγ, IL-2, IL-4, IL-6, IL-7 and IL-15signaling (Non-Patent Document 5). Therefore, regulation of inflammatoryresponses via these signaling pathways is therapeutically promising fortreatment of diseases involving macrophage and lymphocyte activationsuch as autoimmune diseases and acute and chronic organ transplantrejection.

Analyses of JAK2 knockout mice and JAK2-deficient cells suggestinvolvement of JAK2 in various receptor-mediated signaling pathways suchas EPO (Erythropoietin) α, thrombopoietin, IFNγ, IL-3 and GM-CSFsignaling (Non-Patent Documents 6, 7 and 8). These signaling pathwaysare supposed to mediate differentiation of erythrocyte or thrombocyteprogenitor cells in bone marrow. Meanwhile, it is suggested that asubstitution of phenylalanine-617 with valine in JAK2 is associated withmyeloproliferative diseases (Non-Patent Document 6). Therefore,regulation of differentiation of myeloid progenitor cells via thesesignaling pathways is therapeutically promising for treatment ofmyeloproliferative diseases.

The JAK inhibitor CP-690,550 is reported to have improved the pathologyof rheumatoid arthritis and psoriasis in clinical tests (Non-PatentDocuments 9 and 10) and suppressed rejection in a monkey model of kidneytransplantation and airway inflammation in a murine asthma model(Non-Patent Documents 11 and 12). From these findings, immunosuppressionby JAK inhibitors is considered to be useful for prevention or treatmentof organ transplant rejection and post-transplant graft-versus-hostreaction, autoimmune diseases and allergic diseases. Although othercompounds having JAK inhibitory action than CP-690,550 have beenreported (Patent Documents 1 to 11), development of more of suchcompounds is demanded.

PRIOR ART DOCUMENT

-   Patent Document 1: WO01/42246-   Patent Document 2: WO2008/084861-   Patent Document 3: WO2010/119875-   Patent Document 4: WO2011/045702-   Patent Document 5: WO2011/068881-   Patent Document 6: WO2011/075334-   Patent Document 7: WO2007/007919-   Patent Document 8: WO2007/077949-   Patent Document 9: WO2009/152133-   Patent Document 10: WO2011/086053-   Patent Document 11: WO2011/068899-   Non-Patent Document 1: Cell, 2002, 109, pp. S121-131-   Non-Patent Document 2: Science, 2002, 298, pp., 1630-1634-   Non-Patent Document 3: Nature, 1995, 377, pp. 65-68-   Non-Patent Document 4: Science, 1995, 270, pp. 797-800-   Non-Patent Document 5: J. Immunol., 2007, 178, pp. 2623-2629-   Non-Patent Document 6: Pathol. Biol., 2007, 55, pp. 88-91-   Non-Patent Document 7: Cancer Genet. Cytogenet., 2009, 189, pp.    43-47-   Non-Patent Document 8: Semin. Cell. Dev. Biol., 2008, 19, pp.    385-393-   Non-Patent Document 9: Arthritis Rheum., 2009, 60, pp. 1895-1905-   Non-Patent Document 10: J. Invest. Dermatol., 2009, 129, pp.    2299-2302-   Non-Patent Document 11: Science, 2003, 302, pp. 875-878-   Non-Patent Document 12: Eur. J. Pharmacol., 2008, 582, pp. 154-161

DISCLOSURE OF THE INVENTION Technical Problem

The object of the present invention is to provide novel drug compoundshaving excellent JAK inhibitory activities useful for prevention ortreatment of autoimmune diseases, inflammatory diseases and allergicdiseases.

Solution to Problems

As a result of their extensive research in search of newlow-molecular-weight compounds having JAK inhibitory activities, thepresent inventors found that the compounds of the present invention havehigh inhibitory action and accomplished the present invention. Namely,the present invention provide:

(1) A compound represented by the formula (I^(a)):

[wherein the ring A^(a) is represented by the following formula(II^(a)-1) or the formula (II^(a)-2):

(wherein T^(1a) is a nitrogen atom or CR^(4a) U^(1a) is a nitrogen atomor CR^(5a), T^(2a) is a single bond or CR^(7a)R^(8a), and E^(2a) is anoxygen atom or a sulfur atom),X^(a) is a nitrogen atom or CR^(9a),Y^(a) is CR^(10a),R^(1a) is a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group or a C₁₋₆haloalkyl group, the ring B^(a) is a C₃₋₁₁ cycloalkane, a C₃₋₁₁cycloalkene (a ring-constituting methylene group of the C₃₋₁₁cycloalkane and the C₃₋₁₁ cycloalkene may be replaced by a carbonylgroup), a 3 to 14-membered non-aromatic heterocycle, a C₆₋₁₄ aromaticcarbocycle or a 5 to 10-membered aromatic heterocycle,L^(1a) is a single bond, a C₁₋₆ alkylene group, a C₂₋₆ alkenylene groupor a C₂₋₆ alkynylene group (the C₁₋₆ alkylene group, the C₂₋₆ alkenylenegroup and the C₂₋₆ alkynylene group are unsubstituted or substitutedwith one or more identical or different substituents independentlyselected from the group consisting of halogen atoms, hydroxy groups,amino groups, cyano groups and nitro groups),L^(2a) is a single bond, a C₁₋₆ alkylene group, a C₂₋₆ alkenylene group,a C₂₋₆ alkynylene group (the C₁₋₆ alkylene group, the C₂₋₆ alkenylenegroup and the C₂₋₆ alkynylene group are unsubstituted or substitutedwith one or more identical or different substituents independentlyselected from the group consisting of halogen atoms, hydroxy groups,amino groups, cyano groups and nitro groups), ═C(R^(15a))— (whereinR^(15a) is a hydrogen atom or a cyano group, and the bond connecting thering B^(a) and L^(2a) is a double bond) or ═C(R^(15a))—CH₂— (whereinR^(15a) is a hydrogen atom or a cyano group, and the bond connecting thering B^(a) and L^(2a) is a double bond),L^(3a) is a single bond or represented by any of the following formulae(III^(a)-1) to (III^(a)-20) and the formula (XIII^(a)):

(wherein E^(1a) is an oxygen atom, a sulfur atom or NR^(11a)),when L^(3a) is a single bond, R^(2a) is a hydrogen atom, a halogen atom,an azido group, a C₃₋₁₁ cycloalkyl group, a 3 to 14-memberednon-aromatic heterocyclyl group, a C₆₋₁₄ aryl group, a 5 to 10-memberedaromatic heterocyclyl group, a 8 to 14-membered partially saturatedaromatic cyclic group or a 8 to 14-membered aromatic ring-condensedalicyclic hydrocarbon group (the C₃₋₁₁ cycloalkyl group, the 3 to14-membered non-aromatic heterocyclyl group, the C₆₋₁₄ aryl group, the 5to 10-membered aromatic heterocyclyl group, the 8 to 14-memberedpartially saturated aromatic cyclic group and the 8 to 14-memberedaromatic ring-condensed alicyclic hydrocarbon group are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the group consisting of the substituent setV^(4a), substituent set V^(9a) and C₁₋₆ alkyl groups (the C₁₋₆ alkylgroups are substituted with a C₁₋₆ alkoxycarbonylamino group (the C₁₋₆alkoxycarbonylamino group is unsubstituted or substituted with one ormore identical or different halogen atoms independently selected fromthe group consisting of fluorine atoms, chlorine atoms, bromine atomsand iodine atoms))),when L^(3a) is not a single bond, R^(2a) is a hydrogen atom, a C₁₋₆alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group (the C₁₋₆ alkylgroup the C₂₋₆ alkenyl group and the C₂₋₆ alkynyl group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(6a) andthe substituent set V^(9a)), a C₃₋₁₁ cycloalkyl group, a 3 to14-membered non-aromatic heterocyclyl group, a C₆₋₁₄ aryl group, a 5 to10-membered aromatic heterocyclyl group, a 8 to 14-membered partiallysaturated aromatic cyclic group or a 8 to 14-membered aromaticring-condensed alicyclic hydrocarbon group (the C₃₋₁₁ cycloalkyl group,the 3 to 14-membered non-aromatic heterocyclyl group, the C₆₋₁₄ arylgroup, the 5 to 10-membered aromatic heterocyclyl group, the 8 to14-membered partially saturated aromatic cyclic group and the 8 to14-membered aromatic ring-condensed alicyclic hydrocarbon group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(4a) andthe substituent set V^(9a)),n^(a) is 0, 1 or 2,R^(3a) is a hydroxy group, an amino group, a carboxy group, a carbamoylgroup, a sulfamoyl group, a phosphono group, a phosphonooxy group, asulfo group, a sulfoxy group, a tetrazolyl group, a halogen atom, acyano group, a nitro group, a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group,a C₃₋₁₁ cycloalkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ haloalkenylgroup, a C₁₋₆ alkoxy group, a C₁₋₆ haloalkoxy group, a C₁₋₆ alkylthiogroup, a C₁₋₆ haloalkylthio group, a C₁₋₆ alkylcarbonyl group, a C₁₋₆haloalkylcarbonyl group, a C₁₋₆ alkylsulfonyl group, a C₁₋₆haloalkylsulfonyl group, a C₁₋₆ alkoxycarbonyl group, a mono-C₁₋₆alkylamino group, a di-C₁₋₆ alkylamino group, a mono-C₁₋₆alkylaminocarbonyl group, a di-C₁₋₆ alkylaminocarbonyl group or a C₁₋₆alkylcarbonylamino group (when n^(a) is 2, R^(3a)'s may be identical ordifferent),each of R^(4a), R^(5a), R^(7a) and R^(8a) is independently a hydrogenatom, a hydroxy group, an amino group, a carboxy group, a carbamoylgroup, a tetrazolyl group, a halogen atom, a cyano group, a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthiogroup, a C₁₋₆ alkylcarbonyl group, a C₁₋₆ alkylsulfonyl group, amono-C₁₋₆ alkylamino group, a di-C₁₋₆ alkylamino group (the C₁₋₆ alkylgroup, the C₂₋₆ alkenyl group, the C₁₋₆ alkoxy group, the C₁₋₆ alkylthiogroup, the C₁₋₆ alkylcarbonyl group, the C₁₋₆ alkylsulfonyl group, themono-C₁₋₆ alkylamino group and the di-C₁₋₆ alkylamino group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(3a)), aC₁₋₆ alkoxycarbonyl group, a C₃₋₁₁ cycloalkyl group, a 3 to 11-memberednon-aromatic heterocyclyl group, a C₆₋₁₄ aryl group or a 5 to10-membered aromatic heterocyclyl group (the C₃₋₁₁ cycloalkyl group, the3 to 11-membered non-aromatic heterocyclyl group, the C₆₋₁₄ aryl groupand the 5 to 10-membered aromatic heterocyclyl group are unsubstitutedor substituted with one or more identical or different substituentsindependently selected from the substituent set V^(1a)),R^(6a) is a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₁₋₆ alkylcarbonyl group, a C₁₋₆ alkylsulfonyl group, a C₁₋₆alkoxycarbonyl group, a mono-C₁₋₆ alkylaminocarbonyl group, a di-C₁₋₆alkylaminocarbonyl group (the C₁₋₆ alkyl group, the C₂₋₆ alkenyl group,the C₁₋₆ alkylcarbonyl group, the C₁₋₆ alkylsulfonyl group, the C₁₋₆alkoxycarbonyl group, the mono-C₁₋₆ alkylaminocarbonyl group and thedi-C₁₋₆ alkylaminocarbonyl group are unsubstituted or substituted withone or more identical or different substituents independently selectedfrom the substituent set V^(3a)), a C₃₋₁₁ cycloalkyl group, a 3 to11-membered non-aromatic heterocyclyl group, a C₆₋₁₄ aryl group or a 5to 10-membered aromatic heterocyclyl group (the C₃₋₁₁ cycloalkyl group,the 3 to 11-membered non-aromatic heterocyclyl group, the C₆₋₁₄ arylgroup and the 5 to 10-membered aromatic heterocyclyl group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(1a)),each of R^(9a) and R^(10a) is independently a hydrogen atom, a halogenatom, a cyano group, a carbamoyl group, a C₁₋₆ alkyl group, a C₁₋₆haloalkyl group, a C₃₋₁₁ cycloalkyl group, a C₁₋₆ alkoxy group, a C₁₋₆haloalkoxy group, a C₁₋₆ alkylthio group, a C₁₋₆ alkylcarbonyl group, aC₁₋₆ alkylsulfonyl group, a 3 to 11-membered non-aromatic heterocyclylgroup, a C₆₋₁₄ aryl group or a 5 to 10-membered aromatic heterocyclylgroup,R^(11a) is a hydrogen atom, a hydroxy group, a cyano group, a nitrogroup, a C₁₋₆ alkyl group or a C₁₋₆ alkoxy group,each of R^(12a), R^(13a) and R^(14a) is independently a hydrogen atom, aC₁₋₆ alkyl group, a C₁₋₆ haloalkyl group (the C₁₋₆ alkyl group and theC₁₋₆ haloalkyl group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(2a), the substituent set V^(8a) and the substituentset V^(9a)), a C₃₋₁₁ cycloalkyl group, a 3 to 11-membered non-aromaticheterocyclyl group, a C₆₋₁₄ aryl group, a 5 to 10-membered aromaticheterocyclyl group, a 8 to 14-membered partially saturated aromaticcyclic group or a 8 to 14-membered aromatic ring-condensed alicyclichydrocarbon group (the C₃₋₁₁ cycloalkyl group, the 3 to 11-memberednon-aromatic heterocyclyl group, the C₆₋₁₄ aryl group, the 5 to10-membered aromatic heterocyclyl group, the 8 to 14-membered partiallysaturated aromatic cyclic group and the 8 to 14-membered aromaticring-condensed alicyclic hydrocarbon group are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the substituent set V^(4a) and thesubstituent set V^(9a)), the substituent set V^(1a) consists of hydroxygroups, amino groups, carboxy groups, carbamoyl groups, sulfamoylgroups, phosphono groups, phosphonooxy groups, sulfo groups, sulfoxygroups, tetrazolyl groups, halogen atoms, cyano groups, nitro groups,C₁₋₆ alkyl groups, C₁₋₆ haloalkyl groups, C₃₋₁₁ cycloalkyl groups, C₂₋₆alkenyl groups, C₂₋₆ haloalkenyl groups, C₁₋₆ alkoxy groups, C₁₋₆haloalkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆ haloalkylthio groups,C₁₋₆ alkylcarbonyl groups, C₁₋₆ haloalkylcarbonyl groups, C₁₋₆alkylsulfonyl groups, C₁₋₆ haloalkylsulfonyl groups, C₁₋₆ alkoxycarbonylgroups, 3 to 11-membered non-aromatic heterocyclyl groups, mono-C₁₋₆alkylamino groups, di-C₁₋₆ alkylamino groups, mono-C₁₋₆alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups and C₁₋₆alkylcarbonylamino groups,the substituent set V^(2a) consists of the groups in the substituent setV^(1a) and C₆₋₁₄ aryl groups and 5 to 10-membered aromatic heterocyclylgroups (the C₆₋₁₄ aryl groups and 5 to 10-membered aromatic heterocyclylgroups are unsubstituted or substituted with one or more identical ordifferent substituents independently selected from the substituent setV^(1a)),the substituent set V^(3a) consists of hydroxy groups, amino groups,carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups,phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups,halogen atoms, cyano groups, nitro groups, C₁₋₆ alkoxy groups, C₁₋₆haloalkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆ haloalkylthio groups,C₁₋₆ alkylcarbonyl groups, C₁₋₆ haloalkylcarbonyl groups, C₁₋₆alkylsulfonyl groups, C₁₋₆ haloalkylsulfonyl groups, C₁₋₆ alkoxycarbonylgroups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups,mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups,C₁₋₆ alkylcarbonylamino groups, C₃₋₁₁ cycloalkyl groups, 3 to11-membered non-aromatic heterocyclyl groups, C₆₋₁₄ aryl groups and 5 to10-membered aromatic heterocyclyl groups (the C₃₋₁₁ cycloalkyl groups,the 3 to 11-membered non-aromatic heterocyclyl groups, the C₆₋₁₄ arylgroups and the 5 to 10-membered aromatic heterocyclyl groups areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(1a)),the substituent set V^(4a) consists of hydroxy groups, amino groups,carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups,phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups,halogen atoms, cyano groups, nitro groups, C₁₋₆ alkyl groups, C₂₋₆alkenyl groups, C₁₋₆ alkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆alkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆ alkoxycarbonylgroups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups,mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups,C₁₋₆ alkylcarbonylamino groups (the C₁₋₆ alkyl groups, the C₂₋₆ alkenylgroups, the C₁₋₆ alkoxy groups, the C₁₋₆ alkylthio groups, the C₁₋₆alkylcarbonyl groups, the C₁₋₆ alkylsulfonyl groups, the C₁₋₆alkoxycarbonyl groups, the mono-C₁₋₆ alkylamino groups, the di-C₁₋₆alkylamino groups, the mono-C₁₋₆ alkylaminocarbonyl groups, the di-C₁₋₆alkylaminocarbonyl groups and the C₁₋₆ alkylcarbonylamino groups areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(3a)),C₃₋₁₁ cycloalkyl groups, 3 to 11-membered non-aromatic heterocyclylgroups, C₆₋₁₄ aryl groups and 5 to 10-membered aromatic heterocyclylgroups (the C₃₋₁₁ cycloalkyl groups, the 3 to 11-membered non-aromaticheterocyclyl groups, the C₆₋₁₄ aryl group and the 5 to 10-memberedaromatic heterocyclyl groups are unsubstituted or substituted with oneor more identical or different substituents independently selected fromthe substituent set V^(1a)),the substituent set V^(5a) consists of hydroxy groups, amino groups,carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups,phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups,halogen atoms, cyano groups, nitro groups, C₁₋₆ alkoxy groups, C₁₋₆alkylthio groups, C₁₋₆ alkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups,C₁₋₆ alkoxycarbonyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆alkylamino groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆alkylaminocarbonyl groups, C₁₋₆ alkylcarbonylamino groups, C₃₋₁₁cycloalkyl groups, 3 to 11-membered non-aromatic heterocyclyl groups,C₆₋₁₄ aryl group and 5 to 10-membered aromatic heterocyclyl groups (theC₁₋₆ alkoxy groups, the C₁₋₆ alkylthio groups, the C₁₋₆ alkylcarbonylgroups, the C₁₋₆ alkylsulfonyl groups, the C₁₋₆ alkoxycarbonyl groups,the mono-C₁₋₆ alkylamino groups, the di-C₁₋₆ alkylamino groups, themono-C₁₋₆ alkylaminocarbonyl groups, the di-C₁₋₆ alkylaminocarbonylgroups, the C₁₋₆ alkylcarbonylamino groups, the C₃₋₁₁ cycloalkyl groups,the 3 to 11-membered non-aromatic heterocyclyl groups, the C₆₋₁₄ arylgroups and the 5 to 10-membered aromatic heterocyclyl groups areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(3a)),the substituent set V^(6a) consists of hydroxy groups, amino groups,carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups,phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups,halogen atoms, cyano groups, nitro groups, C₁₋₆ alkoxy groups, C₁₋₆alkylthio groups, C₁₋₆ alkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups,C₁₋₆ alkoxycarbonyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆alkylamino groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆alkylaminocarbonyl groups, C₁₋₆ alkylcarbonylamino groups (the C₁₋₆alkoxy groups, the C₁₋₆ alkylthio groups, the C₁₋₆ alkylcarbonyl groups,the C₁₋₆ alkylsulfonyl groups, the C₁₋₆ alkoxycarbonyl groups, themono-C₁₋₆ alkylamino groups, the di-C₁₋₆ alkylamino groups, themono-C₁₋₆ alkylaminocarbonyl groups, the di-C₁₋₆ alkylaminocarbonylgroups and the C₁₋₆ alkylcarbonylamino groups are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the substituent set V^(3a)), C₃₋₁₁cycloalkyl groups, 3 to 11-membered non-aromatic heterocyclyl groups,C₆₋₁₄ aryl groups, 5 to 10-membered aromatic heterocyclyl groups, 8 to14-membered partially saturated aromatic cyclic groups and 8 to14-membered aromatic ring-condensed alicyclic hydrocarbon groups (theC₃₋₁₁ cycloalkyl groups, the 3 to 11-membered non-aromatic heterocyclylgroups, the C₆₋₁₄ aryl groups and the 5 to 10-membered aromaticheterocyclyl groups, the 8 to 14-membered partially saturated aromaticcyclic groups and the 8 to 14-membered aromatic ring-condensed alicyclichydrocarbon groups are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(4a) and the substituent set V^(9a)), the substituentset V^(8a) consists of C₃₋₁₁ cycloalkyl groups, 3 to 11-memberednon-aromatic heterocyclyl groups (the C₃₋₁₁ cycloalkyl groups and 3 to11-membered non-aromatic heterocyclyl groups are substituted with one ormore identical or different substituent independently selected from thesubstituent set V^(2a)), 8 to 14-membered partially saturated aromaticcyclic groups and 8 to 14-membered aromatic ring-condensed alicyclichydrocarbon groups (the 8 to 14-membered partially saturated aromaticcyclic groups and the 8 to 14-membered aromatic ring-condensed alicyclichydrocarbon groups are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(2a)), and the substituent set V^(9a) consists ofmono-C₁₋₆ alkylaminosulfonyl groups, di-C₁₋₆ alkylaminosulfonyl groups,C₁₋₆ alkylsulfonylamino groups, C₁₋₆ alkoxycarbonylamino groups (themono-C₁₋₆ alkylaminosulfonyl groups, the di-C₁₋₆ alkylaminosulfonylgroups the C₁₋₆ alkylsulfonylamino groups and the C₁₋₆alkoxycarbonylamino groups are unsubstituted or substituted with one ormore identical or different substituents independently selected from thesubstituent set V^(3a)), C₃₋₆ cycloalkoxy groups, C₃₋₆ cycloalkylaminogroups, C₃₋₆ cycloalkylthio groups, C₃₋₆ cycloalkylcarbonyl groups andC₃₋₆ cycloalkylsulfonyl groups (the C₃₋₆ cycloalkoxy groups, the C₃₋₆cycloalkylamino groups, the C₃₋₆ cycloalkylthio groups, the C₃₋₆cycloalkylcarbonyl groups and the C₃₋₆ cycloalkylsulfonyl groups areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(2a))], atautomer or a pharmaceutically acceptable salt of the compound or asolvate thereof.(2) The compound according to (1), which is represented by the formula(I^(a)):

[wherein the ring A^(a) is represented by the following formula(II^(a)-1) or the formula (II^(a)-2):

(wherein T^(1a) is a nitrogen atom or CR^(4a) U^(1a) is a nitrogen atomor a CR^(5a), R^(2a) is a single bond or CR^(7a)R^(8a), E^(2a) is anoxygen atom or a sulfur atom),X^(a) is a nitrogen atom or CR^(9a),Y^(a) is CR^(10a),R^(1a) is a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group or a C₁₋₆haloalkyl group, the ring B^(a) is a C₃₋₁₁ cycloalkane, a C₃₋₁₁cycloalkene, a 3 to 11-membered non-aromatic heterocycle, a C₆₋₁₄aromatic carbocycle or a 5 to 10-membered aromatic heterocycle, L^(1a)is a single bond, a C₁₋₆ alkylene group, a C₂₋₆ alkenylene group or aC₂₋₆ alkynylene group (the C₁₋₆ alkylene group, the C₂₋₆ alkenylenegroup and the C₂₋₆ alkynylene group are unsubstituted or substitutedwith one or more identical or different substituents independentlyselected from the group consisting of halogen atoms, hydroxy groups,amino groups, cyano groups and nitro groups),L^(2a) is a single bond, a C₁₋₆ alkylene group, a C₂₋₆ alkenylene groupor a C₂₋₆ alkynylene group (the C₁₋₆ alkylene group, the C₂₋₆ alkenylenegroup and the C₂₋₆ alkynylene group are unsubstituted or substitutedwith one or more identical or different substituents independentlyselected from the group consisting of halogen atoms, hydroxy groups,amino groups, cyano groups and nitro groups),L^(3a) is a single bond or represented by any of the following formulae(III^(a)-1) to (III^(a)-20)

(wherein E^(1a) is an oxygen atom, a sulfur atom or NR^(11a)),when L^(3a) is a single bond, R^(2a) is a hydrogen atom, a halogen atom,a C₃₋₁₁ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclylgroup, a C₆₋₁₄ aryl group or a 5 to 10-membered aromatic heterocyclylgroup (the C₃₋₁₁ cycloalkyl group, the 3 to 11-membered non-aromaticheterocyclyl group, the C₆₋₁₄ aryl group and the 5 to 10-memberedaromatic heterocyclyl group are unsubstituted or substituted with one ormore identical or different substituents independently selected from thesubstituent set V^(4a)),when L^(3a) is not a single bond, R^(2a) is a hydrogen atom, a C₁₋₆alkyl group, a C₂₋₆ alkenyl group (the C₁₋₆ alkyl group and the C₂₋₆alkenyl group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(5a)), a C₃₋₁₁ cycloalkyl group, a 3 to 11-memberednon-aromatic heterocyclyl group, a C₆₋₁₄ aryl group or a 5 to10-membered aromatic heterocyclyl group (the C₃₋₁₁ cycloalkyl group, the3 to 11-membered non-aromatic heterocyclyl group, the C₆₋₁₄ aryl groupand the 5 to 10-membered aromatic heterocyclyl group are unsubstitutedor substituted with one or more identical or different substituentsindependently selected from the substituent set V^(4a)),n^(a) is 0, 1 or 2,R^(3a) is a hydroxy group, an amino group, a carboxy group, a carbamoylgroup, a sulfamoyl group, a phosphono group, a phosphonooxy group, asulfo group, a sulfoxy group, a tetrazolyl group, a halogen atom, acyano group, a nitro group, a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group,a C₃₋₁₁ cycloalkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ haloalkenylgroup, a C₁₋₆ alkoxy group, a C₁₋₆ haloalkoxy group, a C₁₋₆ alkylthiogroup, a C₁₋₆ haloalkylthio group, a C₁₋₆ alkylcarbonyl group, a C₁₋₆haloalkylcarbonyl group, a C₁₋₆ alkylsulfonyl group, a C₁₋₆haloalkylsulfonyl group, a C₁₋₆ alkoxycarbonyl group, a mono-C₁₋₆alkylamino group, a di-C₁₋₆ alkylamino group, a mono-C₁₋₆alkylaminocarbonyl group, a di-C₁₋₆ alkylaminocarbonyl group or a C₁₋₆alkylcarbonylamino group (when n^(a) is 2, R^(3a)'s may be identical ordifferent), each of R^(4a), R^(5a), R^(7a) and R^(8a) is independently ahydrogen atom, a hydroxy group, an amino group, a carboxy group, acarbamoyl group, a tetrazolyl group, a halogen atom, a cyano group, aC₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxy group, a C₁₋₆alkylthio group, a C₁₋₆ alkylcarbonyl group, a C₁₋₆ alkylsulfonyl group,a mono-C₁₋₆ alkylamino group, a di-C₁₋₆ alkylamino group (the C₁₋₆ alkylgroup, the C₂₋₆ alkenyl group, the C₁₋₆ alkoxy group, the C₁₋₆ alkylthiogroup, the C₁₋₆ alkylcarbonyl group, the C₁₋₆ alkylsulfonyl group, themono-C₁₋₆ alkylamino group and the di-C₁₋₆ alkylamino group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(3a)), aC₁₋₆ alkoxycarbonyl group, a C₃₋₁₁ cycloalkyl group, a 3 to 11-memberednon-aromatic heterocyclyl group, a C₆₋₁₄ aryl group or a 5 to10-membered aromatic heterocyclyl group (the C₃₋₁₁ cycloalkyl group, the3 to 11-membered non-aromatic heterocyclyl group, the C₆₋₁₄ aryl groupand the 5 to 10-membered aromatic heterocyclyl group are unsubstitutedor substituted with one or more identical or different substituentsindependently selected from the substituent set V^(1a)),R^(6a) is a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₁₋₆ alkylcarbonyl group, a C₁₋₆ alkylsulfonyl group, a C₁₋₆alkoxycarbonyl group, a mono-C₁₋₆ alkylaminocarbonyl group, a di-C₁₋₆alkylaminocarbonyl group (the C₁₋₆ alkyl group, the C₂₋₆ alkenyl group,the C₁₋₆ alkylcarbonyl group, the C₁₋₆ alkylsulfonyl group, the C₁₋₆alkoxycarbonyl group, the mono-C₁₋₆ alkylaminocarbonyl group and thedi-C₁₋₆ alkylaminocarbonyl group are unsubstituted or substituted withone or more identical or different substituents independently selectedfrom the substituent set V^(3a)), a C₃₋₁₁ cycloalkyl group, a 3 to11-membered non-aromatic heterocyclyl group, a C₆₋₁₄ aryl group or a 5to 10-membered aromatic heterocyclyl group (the C₃₋₁₁ cycloalkyl group,the 3 to 11-membered non-aromatic heterocyclyl group, the C₆₋₁₄ arylgroup and the 5 to 10-membered aromatic heterocyclyl group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(1a)),each of R^(9a) and R^(10a) is independently a hydrogen atom, a halogenatom, a cyano group, a carbamoyl group, a C₁₋₆ alkyl group, a C₁₋₆haloalkyl group, a C₃₋₁₁ cycloalkyl group, a C₁₋₆ alkoxy group, a C₁₋₆haloalkoxy group, a C₁₋₆ alkylthio group, a C₁₋₆ alkylcarbonyl group, aC₁₋₆ alkylsulfonyl group, a 3 to 11-membered non-aromatic heterocyclylgroup, a C₆₋₁₄ aryl group or a 5 to 10-membered aromatic heterocyclylgroup, R^(11a) is a hydrogen atom, a hydroxy group, a cyano group, anitro group, a C₁₋₆ alkyl group or a C₁₋₆ alkoxy group,each of R^(12a), R^(13a) and R^(14a) is independently a hydrogen atom, aC₁₋₆ alkyl group or a C₁₋₆ haloalkyl group (the C₁₋₆ alkyl group and theC₁₋₆ haloalkyl group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(2a)),the substituent set V^(1a) consists of hydroxy groups, amino groups,carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups,phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups,halogen atoms, cyano groups, nitro groups, C₁₋₆ alkyl groups, C₁₋₆haloalkyl groups, C₃₋₁₁ cycloalkyl groups, C₂₋₆ alkenyl groups, C₂₋₆haloalkenyl groups, C₁₋₆ alkoxy groups, C₁₋₆ haloalkoxy groups, C₁₋₆alkylthio groups, C₁₋₆ haloalkylthio groups, C₁₋₆ alkylcarbonyl groups,C₁₋₆ haloalkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆haloalkylsulfonyl groups, C₁₋₆ alkoxycarbonyl groups, 3 to 11-memberednon-aromatic heterocyclyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆alkylamino groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆alkylaminocarbonyl groups and C₁₋₆ alkylcarbonylamino groups,the substituent set V^(2a) consists of the groups in the substituent setV^(1a), C₆₋₁₄ aryl groups and 5 to 10-membered aromatic heterocyclylgroups (the C₆₋₁₄ aryl group and the 5 to 10-membered aromaticheterocyclyl groups are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(1a))the substituent set V^(3a) consists of hydroxy groups, amino groups,carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups,phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups,halogen atoms, cyano groups, nitro groups, C₁₋₆ alkoxy groups, C₁₋₆haloalkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆ haloalkylthio groups,C₁₋₆ alkylcarbonyl groups, C₁₋₆ haloalkylcarbonyl groups, C₁₋₆alkylsulfonyl groups, C₁₋₆ haloalkylsulfonyl groups, C₁₋₆ alkoxycarbonylgroups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups,mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups,C₁₋₆ alkylcarbonylamino groups, C₃₋₁₁ cycloalkyl groups, 3 to11-membered non-aromatic heterocyclyl groups, C₆₋₁₄ aryl groups and 5 to10-membered aromatic heterocyclyl groups (the C₃₋₁₁ cycloalkyl groups,the 3 to 11-membered non-aromatic heterocyclyl groups, the C₆₋₁₄ arylgroups and the 5 to 10-membered aromatic heterocyclyl groups areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(1a)),the substituent set V^(4a) consists of hydroxy groups, amino groups,carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups,phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups,halogen atoms, cyano groups, nitro groups, C₁₋₆ alkyl groups, C₂₋₆alkenyl groups, C₁₋₆ alkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆alkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆ alkoxycarbonylgroups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups,mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups,C₁₋₆ alkylcarbonylamino groups (the C₁₋₆ alkyl groups, the C₂₋₆ alkenylgroups, the C₁₋₆ alkoxy groups, the C₁₋₆ alkylthio groups, the C₁₋₆alkylcarbonyl groups, the C₁₋₆ alkylsulfonyl groups, the C₁₋₆alkoxycarbonyl groups, the mono-C₁₋₆ alkylamino groups, the di-C₁₋₆alkylamino groups, the mono-C₁₋₆ alkylaminocarbonyl groups, the di-C₁₋₆alkylaminocarbonyl groups and the C₁₋₆ alkylcarbonylamino groups areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(3a)),C₃₋₁₁ cycloalkyl groups, 3 to 11-membered non-aromatic heterocyclylgroups, C₆₋₁₄ aryl groups and 5 to 10-membered aromatic heterocyclylgroups (the C₃₋₁₁ cycloalkyl groups, 3 to 11-membered non-aromaticheterocyclyl groups, C₆₋₁₄ aryl groups and 5 to 10-membered aromaticheterocyclyl groups are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(1a)), andthe substituent set V^(5a) consists of hydroxy groups, amino groups,carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups,phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups,halogen atoms, cyano groups, nitro groups, C₁₋₆ alkoxy groups, C₁₋₆alkylthio groups, C₁₋₆ alkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups,C₁₋₆ alkoxycarbonyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆alkylamino groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆alkylaminocarbonyl groups, C₁₋₆ alkylcarbonylamino groups, C₃₋₁₁cycloalkyl groups, 3 to 11-membered non-aromatic heterocyclyl groups,C₆₋₁₄ aryl groups and 5 to 10-membered aromatic heterocyclyl groups (theC₁₋₆ alkoxy groups, the C₁₋₆ alkylthio groups, the C₁₋₆ alkylcarbonylgroups, the C₁₋₆ alkylsulfonyl groups, the C₁₋₆ alkoxycarbonyl groups,the mono-C₁₋₆ alkylamino groups, the di-C₁₋₆ alkylamino groups, themono-C₁₋₆ alkylaminocarbonyl groups, the di-C₁₋₆ alkylaminocarbonylgroups, the C₁₋₆ alkylcarbonylamino groups, the C₃₋₁₁ cycloalkyl groups,the 3 to 11-membered non-aromatic heterocyclyl groups, the C₆₋₁₄ arylgroups and the 5 to 10-membered aromatic heterocyclyl group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(3a))], atautomer or a pharmaceutically acceptable salt of the compound or asolvate thereof.(3) The compound according to (2), wherein R^(1a) is a hydrogen atom, atautomer or a pharmaceutically acceptable salt of the compound or asolvate thereof.(4) The compound according to (2) or (3), wherein Y^(a) is CR^(10a)(wherein R^(10a) is a hydrogen atom), a tautomer or a pharmaceuticallyacceptable salt of the compound or a solvate thereof.(5) The compound according to any one of (2) to (4), wherein X^(a) is anitrogen atom or CR^(9a) (wherein R^(9a) is a hydrogen atom, a halogenatom, a cyano group, a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group or aC₃₋₆ cycloalkyl group), a tautomer or a pharmaceutically acceptable saltof the compound or a solvate thereof.(6) The compound according to any one of (2) to (5), wherein the ringA^(a) is represented by any of the following formulae (IV^(a)-1) to(IV^(a)-3):

(wherein E^(2a) is an oxygen atom or a sulfur atom), a tautomer or apharmaceutically acceptable salt of the compound or a solvate thereof.(7) The compound according to any one of (2) to (6), wherein L^(1a) is asingle bond,L^(2a) is a single bond, a C₁₋₆ alkylene group or a C₂₋₆ alkenylenegroup (the C₁₋₆ alkylene group and the C₂₋₆ alkenylene group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the group consisting of halogenatoms, hydroxy groups, amino groups, cyano groups and nitro groups), thering B^(a) is a C₃₋₁₁ cycloalkane, a C₃₋₁₁ cycloalkene, a 3 to11-membered non-aromatic heterocycle, a C₆₋₁₄ aromatic carbocycle or a 5to 10-membered an aromatic heterocycle,n^(a) is 0 or 1,R^(3a) is a hydroxy group, an amino group, a carboxy group, a carbamoylgroup, a tetrazolyl group, a halogen atom, a cyano group, a nitro group,a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group, a C₃₋₆ cycloalkyl group, aC₁₋₃ alkoxy group, a C₁₋₃ haloalkoxy group or a C₁₋₃ alkylsulfonylgroup,L^(3a) is a single bond, andR^(2a) is a hydrogen atom, a halogen atom, a C₃₋₁₁ cycloalkyl group, a 3to 11-membered non-aromatic heterocyclyl group, a phenyl group, anaphthyl group or a 5 to 10-membered aromatic heterocyclyl group (theC₃₋₁₁ cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclylgroup, the phenyl group, the naphthyl group and the 5 to 10-memberedaromatic heterocyclyl group are unsubstituted or substituted with one ormore identical or different substituents independently selected from thesubstituent set V^(4a)), a tautomer or a pharmaceutically acceptablesalt of the compound or a solvate thereof.(8) The compound according to any one of (2) to (6), wherein L^(1a) is asingle bond or a C₁₋₃ alkylene group,L^(2a) is a single bond or a C₁₋₃ alkylene group (the C₁₋₃ alkylenegroup is unsubstituted or substituted with a cyano group or a C₁₋₃haloalkyl group),the ring B^(a) is a C₃₋₁₁ cycloalkane, a C₃₋₁₁ cycloalkene, a 3 to11-membered non-aromatic heterocycle, benzene or a 5 to 6-memberedaromatic heterocycle,n^(a) is 0 or 1,R^(3a) is a hydroxy group, an amino group, a carboxy group, a carbamoylgroup, a tetrazolyl group, a halogen atom, a cyano group, a nitro group,a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group, a C₃₋₆ cycloalkyl group, aC₁₋₃ alkoxy group, a C₁₋₃ haloalkoxy group ora C₁₋₃ alkylsulfonyl group,L^(3a) is a single bond, andR^(2a) is a hydrogen atom, a halogen atom, a C₃₋₆ cycloalkyl group, a 4to 7-membered non-aromatic heterocyclyl group, a phenyl group or a 5 to6-membered aromatic heterocyclyl group (the C₃₋₆ cycloalkyl group, the 4to 7-membered non-aromatic heterocyclyl group, the phenyl group and the5 to 6-membered aromatic heterocyclyl group are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the substituent set V^(4a)), a tautomer or apharmaceutically acceptable salt of the compound or a solvate thereof.(9) The compound according to (7), wherein the ring B^(a) is a C₃₋₁₁cycloalkane, a 4 to 7-membered non-aromatic heterocycle or benzene,n^(a) is, 0 or 1, andR^(3a) is a hydroxy group, a halogen atom, a cyano group or a C₁₋₃ alkylgroup, a tautomer or a pharmaceutically acceptable salt of the compoundor a solvate thereof.(10) The compound according to (7) or (9), wherein L^(2a) is a singlebond, a C₁₋₆ alkylene group, a C₂₋₆ alkenylene group or a C₁₋₆haloalkylene group (the C₁₋₆ alkylene group, the C₂₋₆ alkenylene groupand the C₁₋₆ haloalkylene group are unsubstituted or substituted withone or two identical or different substituents independently selectedfrom the group consisting of hydroxy groups and cyano groups),the ring B^(a) is a C₃₋₁₁ cycloalkane or a 4 to 7-membered non-aromaticheterocycle, and R^(2a) is a hydrogen atom, a halogen atom, a C₃₋₆cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclyl group, aphenyl group or a 5 to 10-membered aromatic heterocyclyl group (the C₃₋₆cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclyl group,the phenyl group and the 5 to 10-membered aromatic heterocyclyl groupare unsubstituted or substituted with one or more identical or differentsubstituents independently selected from the group consisting of hydroxygroups, amino groups, halogen atoms, cyano groups, nitro groups, carboxygroups, carbamoyl groups, sulfamoyl groups, C₁₋₆ alkyl groups, C₁₋₆alkoxy groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups,C₁₋₆ alkylthio groups, C₁₋₆ alkylcarbonyl groups, C₁₋₆ alkylsulfonylgroups, C₁₋₆ alkoxycarbonyl groups, mono-C₁₋₆ alkylaminocarbonyl groups,alkylaminocarbonyl groups, C₁₋₆ alkylcarbonylamino groups (the C₁₋₆alkyl groups, the C₁₋₆ alkoxy groups, the mono-C₁₋₆ alkylamino groups,the di-C₁₋₆ alkylamino groups, the C₁₋₆ alkylthio groups, the C₁₋₆alkylcarbonyl groups, the C₁₋₆ alkylsulfonyl groups, the C₁₋₆alkoxycarbonyl groups, the mono-C₁₋₆ alkylaminocarbonyl groups, thedi-C₁₋₆ alkylaminocarbonyl groups and the C₁₋₆ alkylcarbonylamino groupsare unsubstituted or substituted with one or more identical or differentsubstituents independently selected from the group consisting of halogenatoms, hydroxy groups, amino groups, cyano groups and C₁₋₃ alkoxygroups), C₃₋₆ cycloalkyl groups, 4 to 7-membered non-aromaticheterocyclyl groups, phenyl groups and 5 to 6-membered aromaticheterocyclyl groups (the C₃₋₆ cycloalkyl groups, the 4 to 7-memberednon-aromatic heterocyclyl groups, the phenyl groups and the 5 to6-membered aromatic heterocyclyl groups are unsubstituted or substitutedwith one or more identical or different substituents independentlyselected from the group consisting of hydroxy groups, halogen atoms,cyano groups, C₁₋₆ alkyl groups and C₁₋₆ haloalkyl groups)), a tautomeror a pharmaceutically acceptable salt of the compound or a solvatethereof.(11) The compound according to (7) or (9), wherein L^(2a) is a singlebond, a C₁₋₃ alkylene group, a C₂₋₃ alkenylene group (the C₁₋₃ alkylenegroup and the C₂₋₃ alkenylene group are unsubstituted or substitutedwith one or two identical or different substituents independentlyselected from the group consisting of hydroxy groups and cyano groups)or a C₁₋₃ haloalkylene group, andR^(2a) is a hydrogen atom or a halogen atom, a tautomer or apharmaceutically acceptable salt of the compound or a solvate thereof.(12) The compound according to any one of (7), (9) and (10), wherein thering B^(a) is a C₄₋₇ cycloalkane or a 4 to 7-membered non-aromaticheterocycle, andR^(2a) is a 3 to 11-membered non-aromatic heterocyclyl group, a phenylgroup or a 5 to 10-membered aromatic heterocyclyl group (the 3 to11-membered non-aromatic heterocyclyl group, the phenyl group and the 5to 10-membered aromatic heterocyclyl group are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the group consisting of hydroxy groups,halogen atoms, cyano groups, carbamoyl groups, C₁₋₃ alkyl groups, C₁₋₃alkoxy groups, mono-C₁₋₃ alkylamino groups, di-C₁₋₃ alkylamino groups(the C₁₋₃ alkyl groups, the C₁₋₃ alkoxy groups, the mono-C₁₋₃ alkylaminogroups and the di-C₁₋₃ alkylamino groups are unsubstituted orsubstituted with a hydroxy group or a cyano group), C₁₋₃ haloalkylgroups, C₁₋₃ haloalkoxy groups, C₁₋₃ alkylthio groups, C₁₋₃haloalkylthio groups, C₁₋₃ alkylsulfonyl groups, C₁₋₃ haloalkylsulfonylgroups, 4 to 7-membered non-aromatic heterocyclyl groups, phenyl groupsand 5 to 6-membered aromatic heterocyclyl groups (the 4 to 7-memberednon-aromatic heterocyclyl groups, the phenyl groups and the 5 to6-membered aromatic heterocyclyl groups are unsubstituted or substitutedwith a substituent selected from the group consisting of a halogen atom,a C₁₋₃ alkyl group and a C₁₋₃ haloalkyl group)), a tautomer or apharmaceutically acceptable salt of the compound or a solvate thereof.(13) The compound according to any one of (7), (9) and (10), wherein thering B^(a) is a C₄₋₇ cycloalkane, andR^(2a) is a 4 to 7-membered non-aromatic heterocyclyl group (the 4 to7-membered non-aromatic heterocyclyl group is unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of hydroxy groups,halogen atoms, cyano groups, carboxy groups, C₁₋₃ alkyl groups (the C₁₋₃alkyl groups are unsubstituted or substituted with a hydroxy group or acyano group), C₁₋₃ haloalkyl groups, C₁₋₃ alkoxy groups, di-C₁₋₃alkylamino groups, mono-C₁₋₃ alkylaminocarbonyl groups, C₁₋₃alkylsulfonyl group, C₁₋₃ alkylcarbonylamino groups (the C₁₋₃ alkoxygroups, the di-C₁₋₃ alkylamino groups, the mono-C₁₋₃ alkylaminocarbonylgroups, the C₁₋₃ alkylsulfonyl group and the C₁₋₃ alkylcarbonylaminogroups are unsubstituted or substituted with one or more identical ordifferent halogen atoms independently selected from the group consistingof fluorine atoms, chlorine atoms, bromine atoms and iodine atoms), 4 to7-membered non-aromatic heterocyclyl groups and phenyl groups (thephenyl groups are unsubstituted or substituted with one or two identicalor different substituents independently selected from the groupconsisting of halogen atoms, C₁₋₃ alkyl groups and C₁₋₃ haloalkylgroups)), a tautomer or a pharmaceutically acceptable salt of thecompound or a solvate thereof.(14) The compound according to any one of (2) to (6), wherein L^(1a) isa single bond, L^(2a) is a single bond, a C₁₋₆ alkylene group or a C₂₋₆alkenylene group (the C₁₋₆ alkylene group and the C₂₋₆ alkenylene groupare unsubstituted or substituted with one or more identical or differentsubstituents independently selected from the group consisting of halogenatoms, hydroxy groups, amino groups, cyano groups and nitro groups), thering B^(a) is a C₃₋₁₁ cycloalkane, a C₃₋₁₁ cycloalkene, a 3 to11-membered non-aromatic heterocycle, a C₆₋₁₄ aromatic carbocycle or a 5to 10-membered aromatic heterocycle,n^(a) is 0 or 1,R^(3a) is a hydroxy group, an amino group, a carboxy group, a carbamoylgroup, a halogen atom, a cyano group, a C₁₋₃ alkyl group, a C₁₋₃haloalkyl group, a C₃₋₆ cycloalkyl group, a C₁₋₃ alkoxy group, a C₁₋₃haloalkoxy group or a C₁₋₃ alkylsulfonyl group,L^(3a) is represented by any of the following formulae (XIV^(a)-1) to(XIV^(a)-15):

(wherein E^(1a) is an oxygen atom, a sulfur atom or NR^(11a) (whereinR^(11a) is a hydroxy group or a C₁₋₃ alkoxy group), each of R^(12a) andR^(13a) is independently a hydrogen atom, a C₁₋₆ alkyl group or a C₁₋₆haloalkyl group (the C₁₋₆ alkyl group and the C₁₋₆ haloalkyl group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the group consisting of hydroxygroups, amino groups, cyano groups, C₃₋₁₁ cycloalkyl groups, C₁₋₆ alkoxygroups, C₁₋₆ haloalkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆alkylsulfonyl groups, C₁₋₆ haloalkylsulfonyl groups, C₁₋₆ alkoxycarbonylgroups, 3 to 11-membered non-aromatic heterocyclyl groups, mono-C₁₋₆alkylamino groups, di-C₁₋₆ alkylamino groups, mono-C₁₋₆alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups, C₁₋₆alkylcarbonylamino groups, phenyl groups and 5 to 10-membered aromaticheterocyclyl groups (the phenyl groups and the 5 to 10-membered aromaticheterocyclyl groups are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(1a)))), andR^(2a) is a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group (theC₁₋₆ alkyl group and the C₂₋₆ alkenyl group are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the substituent set V^(5a)), a C₃₋₁₁cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclyl group, aphenyl group, a naphthyl group or a 5 to 10-membered aromaticheterocyclyl group (the C₃₋₁₁ cycloalkyl group, the 3 to 11-memberednon-aromatic heterocyclyl group, the phenyl group, the naphthyl groupand the 5 to 10-membered aromatic heterocyclyl group are unsubstitutedor substituted with one or more identical or different substituentsindependently selected from the substituent set V^(4a)), a tautomer or apharmaceutically acceptable salt of the compound or a solvate thereof.(15) The compound according to any one of (2) to (6), wherein L^(a) is asingle bond or a C₁₋₃ alkylene group,L^(2a) is a single bond or a C₁₋₃ alkylene group (the C₁₋₃ alkylenegroup is unsubstituted or substituted with a cyano group or a C₁₋₃haloalkylene group), the ring B^(a) is a C₃₋₁₁ cycloalkane, a C₃₋₁₁cycloalkene, a 3 to 11-membered non-aromatic heterocycle, benzene or a 5to 6-membered aromatic heterocycle,n^(a) is 0 or 1R^(3a) is a hydroxy group, an amino group, a carbamoyl group, a halogenatom, a cyano group, a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group, a C₃₋₆cycloalkyl group, a C₁₋₃ alkoxy group, a C₁₋₃ haloalkoxy group or a C₁₋₃alkylsulfonyl group,L^(3a) is represented by any of the following formulae (V^(a)-1) to(V^(a)-11):

(wherein E^(1a) is an oxygen atom, each of R^(12a) and R^(13a) isindependently a hydrogen atom, a C₁₋₆ alkyl group or a C₁₋₆ haloalkylgroup), andR^(2a) is a hydrogen atom, a C₁₋₆ alkyl group (the C₁₋₆ alkyl group isunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(5a)), aC₃₋₆ cycloalkyl group, a 4 to 7-membered non-aromatic heterocyclylgroup, a phenyl group or a 5 to 6-membered aromatic heterocyclyl group(the C₃₋₆ cycloalkyl group, the 4 to 7-membered non-aromaticheterocyclyl group, the phenyl group and the 5 to 6-membered aromaticheterocyclyl group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(1a)), a tautomer or a pharmaceutically acceptablesalt of the compound or a solvate thereof.(16) The compound according to (14), wherein L^(2a) is a single bond, aC₁₋₃ alkylene group, a C₂₋₃ alkenylene group (the C₁₋₃ alkylene groupand the C₂₋₃ alkenylene group are unsubstituted or substituted with oneor two identical or different substituents independently selected fromthe group consisting of hydroxy groups and cyano groups) or a C₁₋₃haloalkylene group,the ring B^(a) is a C₃₋₁₁ cycloalkane, a 4 to 7-membered non-aromaticheterocycle or benzene,n^(a) is 0 or 1,R^(3a) is a halogen atom, a cyano group or a C₁₋₃ alkyl group, andL^(3a) is represented by any of the following formulae (XV^(a)-1) to(XV^(a)-12):

(wherein E^(1a) is an oxygen atom or NR¹¹ (wherein R^(11a) is a hydroxygroup), and R^(12a) is a hydrogen atom, a C₁₋₆ alkyl group or a C₁₋₆haloalkyl group (the C₁₋₆ alkyl group and the C₁₋₆ haloalkyl group isunsubstituted or substituted with a substituent selected from the groupconsisting of a hydroxy group, a cyano group, a C₁₋₃ alkoxy group, aC₃₋₆ cycloalkyl group, a phenyl group and a 5 to 6-membered aromaticheterocyclyl group (the phenyl group and the 5 to 6-membered aromaticheterocyclyl group are unsubstituted or substituted with a substituentselected from the group consisting of a halogen atom, a cyano group, aC₁₋₃ alkyl group and a C₁₋₃ haloalkyl group))), a tautomer or apharmaceutically acceptable salt of the compound or a solvate thereof.(17) The compound according to (14) or (16), wherein L^(2a) is a singlebond or a C₁₋₃ alkylene group,the ring B^(a) is a C₄₋₇ cycloalkane or a 4 to 7-membered non-aromaticheterocycle, and R^(2a) is a hydrogen atom, a C₁₋₆ alkyl group, a C₁₋₆haloalkyl group (the C₁₋₆ alkyl group and the C₁₋₆ haloalkyl group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the group consisting of cyanogroups, hydroxy groups, C₁₋₆ alkoxy groups, mono-C₁₋₆ alkylaminocarbonylgroups, di-C₁₋₆ alkylaminocarbonyl groups (the mono-C₁₋₆alkylaminocarbonyl groups and the di-C₁₋₆ alkylaminocarbonyl groups areunsubstituted or substituted with one or more identical or differenthalogen atoms independently selected from the group consisting offluorine atoms, chlorine atoms, bromine atoms and iodine atoms), C₃₋₆cycloalkyl groups, 4 to 7-membered non-aromatic heterocyclyl groups,phenyl groups or 5 to 10-membered aromatic heterocyclyl groups (the C₃₋₆cycloalkyl groups, the 4 to 7-membered non-aromatic heterocyclyl groups,the phenyl groups and the 5 to 10-membered aromatic heterocyclyl groupsare unsubstituted or substituted with identical or different one, two orthree substituents independently selected from the group consisting ofhydroxy groups, halogen atoms, cyano groups, C₁₋₆ alkoxy groups, C₁₋₆haloalkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆ haloalkylthio groups,C₁₋₆ alkylsulfonyl groups, C₁₋₆ haloalkylsulfonyl groups, C₁₋₆alkoxycarbonyl groups, 4 to 7-membered non-aromatic heterocyclyl groupsand phenyl groups (the phenyl groups are unsubstituted or substitutedwith a halogen atom))), a C₃₋₁₁ cycloalkyl group, a 4 to 7-memberednon-aromatic heterocyclyl group, a phenyl group, a naphthyl group or a 5to 10-membered aromatic heterocyclyl group (the C₃₋₁₁ cycloalkyl group,the 4 to 7-membered non-aromatic heterocyclyl group, the phenyl group,the naphthyl group and the 5 to 10-membered aromatic heterocyclyl groupare unsubstituted or substituted with one, two or three identical ordifferent substituents independently selected from the group consistingof hydroxy groups, halogen atoms, cyano groups, C₁₋₆ alkyl groups (theC₁₋₆ alkyl groups are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thegroup consisting of halogen atoms, cyano groups, hydroxy groups and C₁₋₃alkoxy groups), C₁₋₆ alkoxy groups, C₁₋₆ haloalkoxy groups, C₁₋₆alkylthio groups, C₁₋₆ haloalkylthio groups, C₁₋₆ alkylsulfonyl groups,C₁₋₆ haloalkylsulfonyl groups, C₁₋₆ alkoxycarbonyl groups (the C₁₋₆alkoxycarbonyl groups are unsubstituted or substituted with one or moreidentical or different halogen atoms independently selected from thegroup consisting of fluorine atoms, chlorine atoms, bromine atoms andiodine atoms), 4 to 7-membered non-aromatic heterocyclyl groups andphenyl groups (the phenyl groups are unsubstituted or substituted with ahalogen atom)), a tautomer or a pharmaceutically acceptable salt of thecompound or a solvate thereof.(18) The compound according to any one of (14), (16) and (17), whereinL^(3a) is represented by any of the following formulae (XXIII^(a)-1) to(XXIII^(a)-7):

(wherein E^(1a) is an oxygen atom, and R^(12a) is a hydrogen atom, aC₁₋₃ alkyl group (the C₁₋₃ alkyl group is unsubstituted or substitutedwith a cyano group) or a C₁₋₃ haloalkyl group), andR^(2a) is a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is unsubstituted orsubstituted with a cyano group), a C₁₋₆ haloalkyl group, a C₃₋₆cycloalkyl group, a 4 to 7-membered non-aromatic heterocyclyl group or aphenyl group (the 4 to 7-membered non-aromatic heterocyclyl group andthe phenyl group are unsubstituted or substituted with a substituentselected from the group consisting of a halogen atom, a hydroxy group, acyano group, a C₁₋₃ alkyl group and a C₁₋₃ haloalkyl group), a tautomeror a pharmaceutically acceptable salt of the compound or a solvatethereof.(19) The compound according to any one of (14) and (16) to (18), whereinL^(3a) is represented by any of the following formulae (XXIV^(a)-1) to(XXIV^(a)-4):

(wherein E^(1a) is an oxygen atom, and R^(12a) is a hydrogen atom, aC₁₋₃ alkyl group (the C₁₋₃ alkyl group is unsubstituted or substitutedwith a cyano group) or a C₁₋₃ haloalkyl group), andR^(2a) is a C₁₋₃ alkyl group (the C₁₋₃ alkyl group is unsubstituted orsubstituted with a cyano group), a C₁₋₃ haloalkyl group or a C₃₋₆cycloalkyl group, a tautomer or a pharmaceutically acceptable salt ofthe compound or a solvate thereof.(20) The compound according to any one of (14), (16) and (17), whereinL^(3a) is represented by the formula (XVI^(a)):

(wherein R^(12a) is a hydrogen atom, a C₁₋₃ alkyl group (the C₁₋₃ alkylgroup is unsubstituted or substituted with a substituent selected fromthe group consisting of a hydroxy group, a cyano group, a C₁₋₃ alkoxygroup, a C₃₋₆ cycloalkyl group and a phenyl group) or a C₁₋₃ haloalkylgroup), andR^(2a) is a hydrogen atom, a C₁₋₆ alkyl group (the C₁₋₆ alkyl group isunsubstituted or substituted with one or two identical or differentsubstituents independently selected from the group consisting of cyanogroups, hydroxy groups, C₁₋₃ alkoxy groups, mono-C₁₋₃ alkylaminocarbonylgroups (the mono-C₁₋₃ alkylaminocarbonyl groups are unsubstituted orsubstituted with one or more identical or different halogen atomsindependently selected from the group consisting of fluorine atoms,chlorine atoms, bromine atoms and iodine atoms), C₃₋₆ cycloalkyl groups,4 to 7-membered non-aromatic heterocyclyl groups, phenyl groups and 5 to6-membered aromatic heterocyclyl groups (the C₃₋₆ cycloalkyl groups, the4 to 7-membered non-aromatic heterocyclyl groups, the phenyl groups andthe 5 to 6-membered aromatic heterocyclyl groups are unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of hydroxy groups,halogen atoms, cyano groups, C₁₋₃ alkoxy groups, C₁₋₃ haloalkoxy groups,C₁₋₃ alkylsulfonyl groups, C₁₋₆ alkoxy carbonyl groups and phenyl groups(the phenyl groups are unsubstituted or substituted with a halogenatom))), a C₁₋₆ haloalkyl group (the C₁₋₆ haloalkyl group isunsubstituted or substituted with one or two identical or differentsubstituents independently selected from the group consisting of hydroxygroups, phenyl groups and 5 to 6-membered aromatic heterocyclyl groups(the phenyl groups and the 5 to 6-membered aromatic heterocyclyl groupsare unsubstituted or substituted with one or two identical or differentsubstituents independently selected from the group consisting of halogenatoms, C₁₋₃ alkoxy groups and C₁₋₃ alkylthio groups)), a C₃₋₁₁cycloalkyl group, a 4 to 7-membered non-aromatic heterocyclyl group, aphenyl group or a 5 to 10-membered aromatic heterocyclyl group (theC₃₋₁₁ cycloalkyl group, the 4 to 7-membered non-aromatic heterocyclylgroup, the phenyl group and the 5 to 10-membered aromatic heterocyclylgroup are unsubstituted or substituted with one, two or three identicalor different substituents independently selected from the groupconsisting of hydroxy groups, halogen atoms, cyano groups, C₁₋₃ alkylgroups (the C₁₋₃ alkyl groups are unsubstituted or substituted with asubstituent selected from the group consisting of a hydroxy group, acyano group and a C₁₋₃ alkoxy group), C₁₋₃ haloalkyl groups, C₁₋₃ alkoxygroups, C₁₋₃ haloalkoxy groups, C₁₋₃ alkylsulfonyl groups, C₁₋₃haloalkylsulfonyl groups, C₁₋₆ alkoxycarbonyl groups, 4 to 7-memberednon-aromatic heterocyclyl groups and phenyl groups (the phenyl groupsare unsubstituted or substituted with a halogen atom)), a tautomer or apharmaceutically acceptable salt of the compound or a solvate thereof.(21) The compound according to any one of (2) to (12) and (14) to (19),wherein the ring B^(a) is cyclohexane or piperidine, a tautomer or apharmaceutically acceptable salt of the compound or a solvate thereof.(22) The compound according to (13) or (20), wherein the ring B^(a) iscyclohexane, a tautomer or a pharmaceutically acceptable salt of thecompound or a solvate thereof.(23) The compound according to any one of (5) to (22), wherein r isCR^(9a) (wherein R^(9a) is a hydrogen atom), a tautomer or apharmaceutically acceptable salt of the compound or a solvate thereof.(24) The compound according to any one of (6) to (23), wherein the ringA^(a) is represented by any of the following formulae (IV^(a)-1) to(IV^(a)-3):

(wherein E^(2a) is an oxygen atom or a sulfur atom, and each of R^(4a)and R^(ha) is independently a hydrogen atom or a C₁₋₃ alkyl group), atautomer or a pharmaceutically acceptable salt of the compound or asolvate thereof.(25) The compound according to any one of (8), (23) and (24), whereinL^(1a) is a single bond,L^(2a) is a single bond or a C₁₋₃ alkylene group,the ring B^(a) is a C₄₋₇ cycloalkane, benzene or a 4 to 7-memberednon-aromatic heterocycle,n^(a) is 0,L^(3a) is a single bond, andR^(2a) is a hydrogen atom, a tautomer or a pharmaceutically acceptablesalt of the compound or a solvate thereof.(26) The compound according to any one of (15), (23) and (24), whereinL^(1a) is a single bond,L^(2a) is a single bond,the ring B^(a) is a C₄₋₇ cycloalkane or a 4 to 7-membered non-aromaticheterocycle,n^(a) is 0,L^(3a) is represented by any of the following formulae (VI^(a)-1) to(VI^(a)-3):

andR^(2a) is a hydrogen atom or a C₁₋₃ alkyl group (the C₁₋₃ alkyl group isunsubstituted or substituted with a cyano group or a phenyl group), atautomer or a pharmaceutically acceptable salt of the compound or asolvate thereof.(27) The compound according to any one of (2) to (6), (8), (15), (25)and (26), wherein the ring B^(a) is cyclohexane, benzene or piperidine,a tautomer or a pharmaceutically acceptable salt of the compound or asolvate thereof.(28) The compound according to (1), wherein R^(1a) is a hydrogen atom,X^(a) is CR^(9a) (wherein R^(9a) is a hydrogen atom or a halogen atom),Y^(a) is CR^(10a) (wherein R^(10a) is a hydrogen atom),the ring A^(a) is represented by any of the following formulae(IV^(a)-1) to (IV^(a)-3):

(wherein E^(2a) is an oxygen atom or a sulfur atom, R^(4a) is a hydrogenatom or a C₁₋₃ alkyl group, and R^(6a) is a hydrogen atom),L^(1a) is a single bond,the ring B^(a) is a C₃₋₁₁ cycloalkane, a C₃₋₁₁ cycloalkene (aring-constituting methylene group of the C₃₋₁₁ cycloalkane and the C₃₋₁₁cycloalkene may be replaced by a carbonyl group), a 3 to 11-memberednon-aromatic heterocycle, a C₆₋₁₄ aromatic carbocycle or a 5 to10-membered aromatic heterocycle,n^(a) is 0, 1 or 2,R^(3a) is a hydroxy group, an amino group, a carboxy group, a carbamoylgroup, a halogen atom, a cyano group, a C₁₋₃ alkyl group, a C₁₋₃haloalkyl group or a C₁₋₃ alkoxy group (when n^(a) is 2, R^(3a)'s may beidentical or different),L^(2a) is a single bond, a C₁₋₆ alkylene group, a C₂₋₆ alkenylene group(the C₁₋₆ alkylene group and the C₂₋₆ alkenylene group are unsubstitutedor substituted with one or more identical or different substituentsindependently selected from the group consisting of halogen atoms,hydroxy groups, amino groups, cyano groups and nitro groups),═C(R^(15a))— (wherein R^(15a) is a hydrogen atom or a cyano group, andthe bond connecting the ring B^(a) and L^(2a) is a double bond) or═C(R^(15a))—CH₂— (wherein R^(15a) is a hydrogen atom or a cyano group,and the bond connecting the ring B^(a) and L^(2a) is a double bond),L^(3a) is a single bond or represented by any of the following formulae(XIV^(a)-1) to (XIV^(a)-15) and (XIII^(a))

(wherein E^(1a) is an oxygen atom),when L^(3a) is a single bond, R^(2a) is a hydrogen atom, a halogen atom,an azido group, a C₃₋₁₁ cycloalkyl group, a 3 to 11-memberednon-aromatic heterocyclyl group, a C₆₋₁₄ aryl group, a 5 to 10-memberedaromatic heterocyclyl group, a 8 to 11-membered partially saturatedaromatic cyclic group or a 8 to 11-membered aromatic ring-condensedalicyclic hydrocarbon group (the C₃₋₁₁ cycloalkyl group, the 3 to11-membered non-aromatic heterocyclyl group, the C₆₋₁₄ aryl group, the 5to 10-membered aromatic heterocyclyl group, the 8 to 11-memberedpartially saturated aromatic cyclic group and the 8 to 11-memberedaromatic ring-condensed alicyclic hydrocarbon group are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the group consisting of the substituent setV^(4a), the substituent set V^(9a) and C₁₋₆ alkyl groups (the C₁₋₆ alkylgroups are substituted with a C₁₋₆ alkoxycarbonylamino group (the C₁₋₆alkoxycarbonylamino group is unsubstituted or substituted with one ormore identical or different halogen atoms independently selected fromthe group consisting of fluorine atoms, chlorine atoms, bromine atomsand iodine atoms))),when L^(3a) is not a single bond, R^(2a) is a hydrogen atom, a C₁₋₆alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group (the C₁₋₆ alkylgroup, the C₂₋₆ alkenyl group and the C₂₋₆ alkynyl group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(6a) andthe substituent set V^(9a)), a C₃₋₁₁ cycloalkyl group, a 3 to11-membered non-aromatic heterocyclyl group, a C₆₋₁₄ aryl group, a 5 to10-membered aromatic heterocyclyl group, a 8 to 11-membered partiallysaturated aromatic cyclic group or a 8 to 11-membered aromaticring-condensed alicyclic hydrocarbon group (the C₃₋₁₁ cycloalkyl group,the 3 to 11-membered non-aromatic heterocyclyl group, the C₆₋₁₄ arylgroup, the 5 to 10-membered aromatic heterocyclyl group, the 8 to11-membered partially saturated aromatic cyclic group and the 8 to11-membered aromatic ring-condensed alicyclic hydrocarbon group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(4a) andthe substituent set V^(9a)), and each of R^(12a) and R^(13a) isindependently a hydrogen atom, a C₁₋₆ alkyl group, a C₁₋₆ haloalkylgroup (the C₁₋₆ alkyl group and the C₁₋₆ haloalkyl group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(2a), thesubstituent set V^(8a) and the substituent set V^(9a)), a C₃₋₁₁cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclyl group, aC₆₋₁₄ aryl group, a 5 to 10-membered aromatic heterocyclyl group or a 8to 11-membered partially saturated aromatic cyclic group (the C₃₋₁₁cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclyl group,the C₆₋₁₄ aryl group, the 5 to 10-membered aromatic heterocyclyl groupand the 8 to 11-membered partially saturated aromatic cyclic group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(4a) andthe substituent set V^(9a)), a tautomer or a pharmaceutically acceptablesalt of the compound or a solvate thereof.(29) The compound according to (1) or (28), wherein L^(2a) is a singlebond, a C₁₋₆ alkylene group, a C₂₋₆ alkenylene group (the C₁₋₆ alkylenegroup and the C₂₋₆ alkenylene group are unsubstituted or substitutedwith one or two identical or different substituents independentlyselected from the group consisting of hydroxy groups and cyano groups)or a C₁₋₆ haloalkylene group,the ring B^(a) is a C₄₋₇ cycloalkane (a ring-constituting methylenegroup of the C₄₋₇ cycloalkane may be replaced by a carbonyl group) or a4 to 7-membered non-aromatic heterocycle,n^(a) is 0, 1 or 2,R^(3a) is a cyano group, a C₁₋₃ alkyl group or a halogen atom (whenn^(a) is 2, R^(3a)'s may be identical or different), a tautomer or apharmaceutically acceptable salt of the compound or a solvate thereof.(30) The compound according to any one of (1), (28) and (29), whereinL^(3a) is a single bond,R^(2a) is a hydrogen atom, a halogen atom, an azido group, a C₃₋₁₁cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclyl group, aphenyl group, a 5 to 10-membered aromatic heterocyclyl group or a 8 to11-membered partially saturated aromatic cyclic group (the C₃₋₁₁cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclyl group,the phenyl group, the 5 to 10-membered aromatic heterocyclyl group andthe 8 to 11-membered partially saturated aromatic cyclic group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the group consisting of thesubstituent set V^(4a), the substituent set V^(9a) and C₁₋₆ alkyl groups(the C₁₋₆ alkyl groups are substituted with a C₁₋₆ alkoxycarbonylaminogroup (the C₁₋₆ alkoxycarbonylamino group is unsubstituted orsubstituted with one or more identical or different halogen atomsindependently selected from the group consisting of fluorine atoms,chlorine atoms, bromine atoms and iodine atoms))), a tautomer or apharmaceutically acceptable salt of the compound or a solvate thereof.(31) The compound according to (30), wherein L^(2a) is a C₁₋₃ alkylenegroup, the ring B^(a) is a 4 to 7-membered non-aromatic heterocycle,L^(3a) is a single bond,R^(2a) is a phenyl group or a 5 to 10-membered aromatic heterocyclylgroup or a 8 to 11-membered partially saturated aromatic cyclic group(the phenyl group, the 5 to 10-membered aromatic heterocyclyl group andthe 8 to 11-membered partially saturated aromatic cyclic group areunsubstituted or substituted with one, two or three identical ordifferent substituents independently selected from the group consistingof hydroxy groups, halogen atoms, cyano groups, carbamoyl groups, C₁₋₆alkyl groups, C₁₋₆ haloalkyl groups, C₁₋₆ alkoxy groups, C₁₋₆ haloalkoxygroups, di-C₁₋₆ alkylamino groups, C₁₋₆ alkylthio groups, C₁₋₆haloalkylthio groups, C₁₋₆ alkylsulfonyl groups, 4 to 7-memberednon-aromatic heterocyclyl groups and 5 to 6-membered aromaticheterocyclyl groups), a tautomer or a pharmaceutically acceptable saltof the compound or a solvate thereof.(32) The compound according to any one of (28) to (30), wherein the ringB^(a) is a C₄₋₇ cycloalkane,L^(3a) is a single bond,R^(2a) is a 3 to 11-membered non-aromatic heterocyclyl group (the 3 to11-membered non-aromatic heterocyclyl group is unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the group consisting of hydroxy groups,amino groups, halogen atoms, cyano groups, carbamoyl groups, carboxygroups, C₁₋₆ alkyl groups (the C₁₋₆ alkyl groups are unsubstituted orsubstituted with one or more identical or different halogen atomsindependently selected from the group consisting of fluorine atoms,chlorine atoms, bromine atoms and iodine atoms or with a substituentselected from the group consisting of a hydroxy group, a cyano group anda C₁₋₆ alkoxycarbonylamino group), C₁₋₃ alkoxy groups, mono-C₁₋₃alkylaminocarbonyl groups, C₁₋₃ alkylcarbonylamino groups (the C₁₋₃alkoxy groups, the mono-C₁₋₃ alkylaminocarbonyl groups, the C₁₋₃alkylcarbonylamino groups are unsubstituted or substituted with one ormore identical or different halogen atoms independently selected fromthe group consisting of fluorine atoms, chlorine atoms, bromine atomsand iodine atoms), di-C₁₋₃ alkylamino groups, C₁₋₃ alkylsulfonyl groups,di-C₁₋₃ alkylaminosulfonyl groups, C₁₋₆ alkoxycarbonylamino groups, 4 to7-membered non-aromatic heterocyclyl groups and phenyl groups (thephenyl groups are unsubstituted or substituted with a halogen atom)), atautomer or a pharmaceutically acceptable salt of the compound or asolvate thereof.(33) The compound according to any one of (1), (28) and (29), whereinL^(3a) is represented by any of the following formulae (XV^(a)-1) to(XV^(a)-12) and (XIII^(a)):

(wherein E^(1a) is an oxygen atom, and R^(12a) is a hydrogen atom, aC₁₋₆ alkyl group (the C₁₋₆ alkyl group is unsubstituted or substitutedwith a substituent selected from the group consisting of a hydroxygroup, a cyano group, a C₁₋₃ alkoxy group, a C₃₋₆ cycloalkyl group, aphenyl group and a 5 to 6-membered aromatic heterocyclyl group (thephenyl group and the 5 to 6-membered aromatic heterocyclyl group areunsubstituted or substituted with a substituent selected from the groupconsisting of a halogen atom, a cyano group, a C₁₋₃ alkyl group and aC₁₋₃ haloalkyl group)), a C₁₋₆ haloalkyl group, a C₃₋₆ cycloalkyl groupor a phenyl group (the phenyl group is unsubstituted or substituted witha halogen atom or a cyano group)),R^(2a) is a hydrogen atom, a C₁₋₆ alkyl group (the C₁₋₆ alkyl group isunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(6a) andthe substituent set V^(9a)), a C₂₋₆ alkynyl group, a C₃₋₁₁ cycloalkylgroup, a 3 to 11-membered non-aromatic heterocyclyl group, a phenylgroup, a 5 to 10-membered aromatic heterocyclyl group, a 8 to11-membered partially saturated aromatic cyclic group or a 8 to11-membered aromatic ring-condensed alicyclic hydrocarbon group (theC₃₋₁₁ cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclylgroup, the phenyl group, the 5 to 10-membered aromatic heterocyclylgroup, the 8 to 11-membered partially saturated aromatic cyclic groupand the 8 to 11-membered aromatic ring-condensed alicyclic hydrocarbongroup are unsubstituted or substituted with one or more identical ordifferent substituents independently selected from the substituent setV^(4a) and the substituent set V^(9a)), a tautomer or a pharmaceuticallyacceptable salt of the compound or a solvate thereof.(34) The compound according to (33), wherein the ring B^(a) is a C₄₋₇cycloalkane or a 4 to 7-membered non-aromatic heterocycle,L^(3a) is represented by the following formulae (XXV^(a)-1) or(XXV^(a)-2):

(wherein R^(12a) is a hydrogen atom, a C₁₋₃ alkyl group (the C₁₋₃ alkylgroup is unsubstituted or substituted with a substituent selected fromthe group consisting of a hydroxy group, a cyano group, a C₁₋₃ alkoxygroup, a C₃₋₆ cycloalkyl group and a phenyl group), a C₁₋₃ haloalkylgroup, a C₃₋₆ cycloalkyl group or a phenyl group (the phenyl group isunsubstituted or substituted with a halogen atom or a cyano group)),R^(2a) is a hydrogen atom, a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group(the C₁₋₆ alkyl group and the C₁₋₆ haloalkyl group are unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of hydroxy groups,cyano groups, C₁₋₃ alkoxy groups, C₁₋₃ alkylthio groups, C₁₋₃alkylsulfonyl groups, mono-C₁₋₃ alkylaminocarbonyl groups, di-C₁₋₃alkylaminocarbonyl groups (the mono-C₁₋₃ alkylaminocarbonyl groups andthe di-C₁₋₃ alkylaminocarbonyl groups are unsubstituted or substitutedwith one or more identical or different halogen atoms independentlyselected from the group consisting of fluorine atoms, chlorine atoms,bromine atoms and iodine atoms), C₃₋₆ cycloalkyl groups, 4 to 7-memberednon-aromatic heterocyclyl groups, phenyl groups and 5 to 6-memberedaromatic heterocyclyl groups (the C₃₋₆ cycloalkyl groups, the 4 to7-membered non-aromatic heterocyclyl groups, the phenyl groups and the 5to 6-membered aromatic heterocyclyl groups are unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of hydroxy groups,amino groups, halogen atoms, cyano groups, C₁₋₃ alkyl groups, C₁₋₃haloalkyl groups, C₁₋₃ alkoxy groups, C₁₋₃ haloalkoxy groups, C₁₋₃alkylthio groups, C₁₋₃ haloalkylthio groups, C₁₋₃ alkylsulfonyl groups,C₁₋₃ haloalkylsulfonyl groups, C₁₋₆ alkoxycarbonyl groups, mono-C₁₋₃alkylamino groups, di-C₁₋₃ alkylamino groups, mono-C₁₋₃alkylaminocarbonyl groups, di-C₁₋₃ alkylaminocarbonyl groups, C₁₋₃alkylcarbonylamino group (the C₁₋₆ alkoxycarbonyl groups, the mono-C₁₋₃alkylamino groups, the di-C₁₋₃ alkylamino groups, the mono-C₁₋₃alkylaminocarbonyl groups, the di-C₁₋₃ alkylaminocarbonyl groups and theC₁₋₃ alkylcarbonylamino group are unsubstituted or substituted with oneor more identical or different halogen atoms independently selected fromthe group consisting of fluorine atoms, chlorine atoms, bromine atomsand iodine atoms), 4 to 7-membered non-aromatic heterocyclyl groups,phenyl groups (the phenyl groups are unsubstituted or substituted with ahalogen atom) and 5 to 6-membered aromatic heterocyclyl groups)), a C₂₋₆alkynyl group, a C₃₋₆ cycloalkyl group, a 4 to 7-membered non-aromaticheterocyclyl group, a phenyl group, a 8 to 11-membered partiallysaturated aromatic cyclic group or a 8 to 11-membered aromaticring-condensed alicyclic hydrocarbon group (the C₃₋₆ cycloalkyl group,the 4 to 7-membered non-aromatic heterocyclyl group, the phenyl group,the 8 to 11-membered partially saturated aromatic cyclic group and the 8to 11-membered aromatic ring-condensed alicyclic hydrocarbon group areunsubstituted or substituted with one, two or three identical ordifferent substituents independently selected from the group consistingof hydroxy groups, amino groups, halogen atoms, cyano groups, C₁₋₃ alkylgroups (the C₁₋₃ alkyl groups are unsubstituted or substituted with asubstituent selected from the group consisting of a hydroxy group, acyano group and a C₁₋₃ alkoxy group), C₁₋₃ haloalkyl groups, C₁₋₃ alkoxygroups, C₁₋₃ haloalkoxy groups, C₁₋₃ alkylthio groups, C₁₋₃haloalkylthio groups, C₁₋₃ alkylsulfonyl groups, C₁₋₃ haloalkylsulfonylgroups, C₁₋₆ alkoxycarbonyl groups, mono-C₁₋₃ alkylamino groups, di-C₁₋₃alkylamino groups, mono-C₁₋₃ alkylaminocarbonyl groups, di-C₁₋₃alkylaminocarbonyl groups, C₁₋₃ alkylcarbonylamino groups (the C₁₋₆alkoxycarbonyl groups, the mono-C₁₋₃ alkylamino groups, the di-C₁₋₃alkylamino groups, the mono-C₁₋₃ alkylaminocarbonyl groups, the di-C₁₋₃alkylaminocarbonyl groups and the C₁₋₃ alkylcarbonylamino group areunsubstituted or substituted with one or more identical or differenthalogen atoms independently selected from the group consisting offluorine atoms, chlorine atoms, bromine atoms and iodine atoms), 4 to7-membered non-aromatic heterocyclyl groups and phenyl groups (thephenyl groups are unsubstituted or substituted with a halogen atom)), atautomer or a pharmaceutically acceptable salt of the compound or asolvate thereof.(35) The compound according to (33), wherein the ring B^(a) is a C₄₋₇cycloalkane,L^(3a) is represented by any of the following formulae (XXVI^(a)-1) to(XXVI^(a)-5):

(wherein E^(1a) is an oxygen atom, and R^(12a) is a hydrogen atom, aC₁₋₃ alkyl group (the C₁₋₃ alkyl group is unsubstituted or substitutedwith a substituent selected from the group consisting of a hydroxygroup, a cyano group, a C₁₋₃ alkoxy group, a C₃₋₆ cycloalkyl group, aphenyl group and a 5 to 6-membered aromatic heterocyclyl group (the 5 to6-membered aromatic heterocyclyl group is unsubstituted or substitutedwith a C₁₋₃ alkyl group)), a C₁₋₃ haloalkyl group, a C₃₋₆ cycloalkylgroup or a phenyl group (the phenyl group is unsubstituted orsubstituted with a halogen atom or a cyano group)), andR^(2a) is a C₁₋₃ alkyl group (the C₁₋₃ alkyl group is unsubstituted orsubstituted with a cyano group), a C₁₋₃ haloalkyl group or a C₃₋₆cycloalkyl group, a tautomer or a pharmaceutically acceptable salt ofthe compound or a solvate thereof.(36) The compound according to (34) or (35), wherein L^(3a) isrepresented by the formula (XVI^(a)):

(wherein R^(12a) is a hydrogen atom, a C₁₋₃ alkyl group (the C₁₋₃ alkylgroup is unsubstituted or substituted with a substituent selected fromthe group consisting of a hydroxy group, a cyano group, a C₁₋₃ alkoxygroup, a C₃₋₆ cycloalkyl group and a phenyl group), a C₁₋₃ haloalkylgroup, a C₃₋₆ cycloalkyl group or a phenyl group (the phenyl group isunsubstituted or substituted with a halogen atom or a cyano group)), atautomer or a pharmaceutically acceptable salt of the compound or asolvate thereof.(37) The compound according to (33), wherein L^(3a) is represented bythe formula (XIII^(a)):

(wherein E^(1a) is an oxygen atom),R^(2a) is a C₁₋₃ alkyl group, a tautomer or a pharmaceuticallyacceptable salt of the compound or a solvate thereof.(38) The compound according to any one of (1) to (24), (28) to (30) and(32) to (37),wherein L^(2a) is a single bond or a C₁₋₃ alkylene group, a tautomer ora pharmaceutically acceptable salt of the compound or a solvate thereof.(39) The compound according to (1) or (28), wherein L^(1a) is a singlebond,the ring B^(a) is a C₄₋₇ cycloalkane,L^(2a) is =C(R^(15a))—(wherein R^(15a) is a hydrogen atom or a cyanogroup, and the bond connecting the ring B^(a) and L^(2a) is a doublebond) or ═C(R^(15a))—CH₂— (wherein R^(15a) is a hydrogen atom or a cyanogroup, and the bond connecting the ring B^(a) and L^(2a) is a doublebond), andwhen L^(3a) is a single bond, R^(2a) is a hydrogen atom, andwhen L^(3a) is the formula (X^(a)-2):

R^(2a) is a C₁₋₃ alkyl group,a tautomer or a pharmaceutically acceptable salt of the compound or asolvate thereof.(40) The compound according to any one of (1) to (39), wherein n^(a) is0, a tautomer or a pharmaceutically acceptable salt of the compound or asolvate thereof.(41) A compound represented by the formula (I^(b)):

[wherein the ring A^(b) is represented by the formula (II^(b)):

(wherein T^(1b) is CR^(4b)R^(5b), C(═O), C(═S), C(═NR^(17b)), a sulfuratom, S(═O) or S(═O)₂, U^(1b) is a nitrogen atom or CR^(6b), and \N^(1b)is a nitrogen atom or CR^(8b)), the formula (III^(b)):

(wherein T^(2b) is CR^(4b), U^(2b) is a nitrogen atom or CR^(6b), andW^(2b) is CR^(8b)R^(9b), C(═O), C(═S), C(═NR^(17b)), NR^(10b) an oxygenatom, a sulfur atom, S(═O) or S(═O)₂ (provided that when U^(2b) isCR^(6b), W^(2b) is not C(═O))) or the formula (IV^(b)):

(wherein T^(3b) is CR^(4b)R^(5b), C(═O), C(═S), C(═NR^(17b)), a sulfuratom, S(═O) or S(═O)₂, U^(3b) is CR^(6b)R^(7b), C(═O), C(═S),C(═NR^(17b)), NR^(10b), an oxygen atom, a sulfur atom, S(═O) or S(═O)₂,and W^(3b) is CR^(8b)R^(9b), C(═O), C(═S), C(═NR^(17b)), NR^(11b), anoxygen atom, a sulfur atom, S(═O) or S(═O)₂ (provided that when T^(3b)is CR^(4b)R^(5b) and U^(3b) is CR^(6b)R^(7b), W^(3b) is notCR^(8b)R^(9b))),X^(b) is a nitrogen atom or CR^(16b),Y^(b) is CR^(16b),R^(1b) is a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group or a C₁₋₆haloalkyl group, the ring B^(b) is a C₃₋₁₁ cycloalkene, a C₃₋₁₁cycloalkene, a 3 to 11-membered non-aromatic heterocycle, a C₆₋₁₄aromatic carbocycle or a 5 to 10-membered aromatic heterocycle, L^(1b)is a single bond, a C₁₋₆ alkylene group, a C₂₋₆ alkenylene group or aC₂₋₆ alkynylene group (the C₁₋₆ alkylene group, the C₂₋₆ alkenylenegroup and the C₂₋₆ alkynylene group are unsubstituted or substitutedwith one or more identical or different substituents independentlyselected from the group consisting of halogen atoms, hydroxy groups,amino groups, cyano groups and nitro groups),L^(2b) is a single bond, a C₁₋₆ alkylene group, a C₂₋₆ alkenylene groupor a C₂₋₆ alkynylene group (the C₁₋₆ alkylene group, the C₂₋₆ alkenylenegroup and the C₂₋₆ alkynylene group are unsubstituted or substitutedwith one or more identical or different substituents independentlyselected from the group consisting of halogen atoms, hydroxy groups,amino groups, cyano groups and nitro groups),L^(3b) is a single bond or represented by any of the following formulae(V^(b)-1) to (V^(b)-20):

(wherein E^(1b) is an oxygen atom, a sulfur atom or NR^(18b)),when L^(3b) is a single bond, R^(2b) is a hydrogen atom, a halogen atom,a C₃₋₁₁ cycloalkyl group, a 3 to 14-membered non-aromatic heterocyclylgroup, a C₆₋₁₄ aryl group, a 5 to 10-membered aromatic heterocyclylgroup, a 8 to 14-membered partially saturated aromatic cyclic group or a8 to 14-membered aromatic ring-condensed alicyclic hydrocarbon group(the C₃₋₁₁ cycloalkyl group, the 3 to 14-membered non-aromaticheterocyclyl group, the C₆₋₁₄ aryl group, the 5 to 10-membered aromaticheterocyclyl group, the 8 to 14-membered partially saturated aromaticcyclic group and the 8 to 14-membered aromatic ring-condensed alicyclichydrocarbon group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(4b) and the substituent set V^(9b)),when L^(3b) is not a single bond, R^(2b) is a hydrogen atom, a C₁₋₆alkyl group, a C₂₋₆ alkenyl group (the C₁₋₆ alkyl group and the C₂₋₆alkenyl group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(6b) and the substituent set V^(9b)), a C₃₋₁₁cycloalkyl group, a 3 to 14-membered non-aromatic heterocyclyl group, aC₆₋₁₄ aryl group, a 5 to 10-membered aromatic heterocyclyl group, a 8 to14-membered partially saturated aromatic cyclic group or a 8 to14-membered aromatic ring-condensed alicyclic hydrocarbon group (theC₃₋₁₁ cycloalkyl group, the 3 to 14-membered non-aromatic heterocyclylgroup, the C₆₋₁₄ aryl group, the 5 to 10-membered aromatic heterocyclylgroup, the 8 to 14-membered partially saturated aromatic cyclic groupand the 8 to 14-membered aromatic ring-condensed alicyclic hydrocarbongroup are unsubstituted or substituted with one or more identical ordifferent substituents independently selected from the substituent setV^(4b) and substituent set V^(9b)),n^(b) is 0, 1 or 2,R^(3b) is a hydroxy group, an amino group, a carboxy group, a carbamoylgroup, a sulfamoyl group, a phosphono group, a phosphonooxy group, asulfo group, a sulfoxy group, a tetrazolyl group, a halogen atom, acyano group, a nitro group, a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group,a C₃₋₁₁ cycloalkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ haloalkenylgroup, a C₁₋₆ alkoxy group, a C₁₋₆ haloalkoxy group, a C₁₋₆ alkylthiogroup, a C₁₋₆ haloalkylthio group, a C₁₋₆ alkylcarbonyl group, a C₁₋₆haloalkylcarbonyl group, a C₁₋₆ alkylsulfonyl group, a C₁₋₆haloalkylsulfonyl group, a C₁₋₆ alkoxycarbonyl group, a mono-C₁₋₆alkylamino group, a di-C₁₋₆ alkylamino group, a mono-C₁₋₆alkylaminocarbonyl group, a di-C₁₋₆ alkylaminocarbonyl group or a C₁₋₆alkylcarbonylamino group (when n^(b) is 2, R^(3b)'s may be identical ordifferent), each of R^(4b), R^(5b), R^(6b), R^(7b), R^(8b) and R^(9b) isindependently a hydrogen atom, a hydroxy group, an amino group, acarboxy group, a carbamoyl group, a tetrazolyl group, a halogen atom, acyano group, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxygroup, a C₁₋₆ alkylthio group, a C₁₋₆ alkylcarbonyl group, a C₁₋₆alkylsulfonyl group, a mono-C₁₋₆ alkylamino group, a di-C₁₋₆ alkylaminogroup (the C₁₋₆ alkyl group, the C₂₋₆ alkenyl group, the C₁₋₆ alkoxygroup, the C₁₋₆ alkylthio group, the C₁₋₆ alkylcarbonyl group, the C₁₋₆alkylsulfonyl group, the mono-C₁₋₆ alkylamino group and the di-C₁₋₆alkylamino group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(3b)), a C₁₋₆ alkoxycarbonyl group, a C₃₋₁₁ cycloalkylgroup, a 3 to 11-membered non-aromatic heterocyclyl group, a C₆₋₁₄ arylgroup or a 5 to 10-membered aromatic heterocyclyl group (the C₃₋₁₁cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclyl group,the C₆₋₁₄ aryl group and the 5 to 10-membered aromatic heterocyclylgroup are unsubstituted or substituted with one or more identical ordifferent substituents independently selected from the substituent setV^(1b)),each of R^(10b) and R^(11b) is independently a hydrogen atom, a C₁₋₆alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkylcarbonyl group, a C₁₋₆alkylsulfonyl group, a C₁₋₆ alkoxycarbonyl group, a mono-C₁₋₆alkylaminocarbonyl group, a di-C₁₋₆ alkylaminocarbonyl group (the C₁₋₆alkyl group, the C₂₋₆ alkenyl group, the C₁₋₆ alkylcarbonyl group, theC₁₋₆ alkylsulfonyl group, the C₁₋₆ alkoxycarbonyl group, the mono-C₁₋₆alkylaminocarbonyl group and the di-C₁₋₆ alkylaminocarbonyl group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(3b)), aC₃₋₁₁ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclylgroup, a C₆₋₁₄ aryl group or a 5 to 10-membered aromatic heterocyclylgroup (the C₃₋₁₁ cycloalkyl group, the 3 to 11-membered non-aromaticheterocyclyl group, the C₆₋₁₄ aryl group and the 5 to 10-memberedaromatic heterocyclyl group are unsubstituted or substituted with one ormore identical or different substituents independently selected from thesubstituent set V^(1b)),each of R^(12b), R^(13b) and R^(14b) is independently a hydrogen atom, aC₁₋₆ alkyl group or a C₁₋₆ haloalkyl group (the C₁₋₆ alkyl group and theC₁₋₆ haloalkyl group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(3b), the substituent set V^(8b) and the substituentset V^(9b)), each of R^(15b) and R^(16b) is independently a hydrogenatom, a halogen atom, a cyano group, a carbamoyl group, a C₁₋₆ alkylgroup, a C₁₋₆ haloalkyl group, a C₃₋₁₁ cycloalkyl group, a C₁₋₆ alkoxygroup, a C₁₋₆ haloalkoxy group, a C₁₋₆ alkylthio group, a C₁₋₆alkylcarbonyl group, a C₁₋₆ alkylsulfonyl group, a 3 to 11-memberednon-aromatic heterocyclyl group, a C₆₋₁₄ aryl group or a 5 to10-membered aromatic heterocyclyl group,each of R^(17b) and R^(18b) is independently a hydrogen atom, a hydroxygroup, a cyano group, a nitro group, a C₁₋₆ alkyl group or a C₁₋₆ alkoxygroup,the substituent set V^(1b) consists of hydroxy groups, amino groups,carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups,phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups,halogen atoms, cyano groups, nitro groups, C₁₋₆ alkyl groups, C₁₋₆haloalkyl groups, C₃₋₁₁ cycloalkyl groups, C₂₋₆ alkenyl groups, C₂₋₆haloalkenyl groups, C₁₋₆ alkoxy groups, C₁₋₆ haloalkoxy groups, C₁₋₆alkylthio groups, C₁₋₆ haloalkylthio groups, C₁₋₆ alkylcarbonyl groups,C₁₋₆ haloalkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆haloalkylsulfonyl groups, C₁₋₆ alkoxycarbonyl groups, 3 to 11-memberednon-aromatic heterocyclyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆alkylamino groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆alkylaminocarbonyl groups and C₁₋₆ alkylcarbonylamino groups,the substituent set V^(2b) consists of the groups in the substituent setV^(1b), and C₆₋₁₄ aryl groups and 5 to 10-membered aromatic heterocyclylgroups (the C₆₋₁₄ aryl groups and the 5 to 10-membered aromaticheterocyclyl groups are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(1b)),the substituent set V^(3b) consists of hydroxy groups, amino groups,carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups,phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups,halogen atoms, cyano groups, nitro groups, C₁₋₆ alkoxy groups, C₁₋₆haloalkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆ haloalkylthio groups,C₁₋₆ alkylcarbonyl groups, C₁₋₆ haloalkylcarbonyl groups, C₁₋₆alkylsulfonyl groups, C₁₋₆ haloalkylsulfonyl groups, C₁₋₆ alkoxycarbonylgroups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups,mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups,C₁₋₆ alkylcarbonylamino groups, C₃₋₁₁ cycloalkyl groups, 3 to11-membered non-aromatic heterocyclyl groups, C₆₋₁₄ aryl group and 5 to10-membered aromatic heterocyclyl groups (the C₃₋₁₁ cycloalkyl groups,the 3 to 11-membered non-aromatic heterocyclyl groups, the C₆₋₁₄ arylgroups and the 5 to 10-membered aromatic heterocyclyl groups areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(1b)),the substituent set V^(4b) consists of hydroxy groups, amino groups,carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups,phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups,halogen atoms, cyano groups, nitro groups, C₁₋₆ alkyl groups, C₂₋₆alkenyl groups, C₁₋₆ alkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆alkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆ alkoxycarbonylgroups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups,mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups,C₁₋₆ alkylcarbonylamino groups (the C₁₋₆ alkyl groups, the C₂₋₆ alkenylgroups, the C₁₋₆ alkoxy groups, the C₁₋₆ alkylthio groups, the C₁₋₆alkylcarbonyl groups, the C₁₋₆ alkylsulfonyl groups, the C₁₋₆alkoxycarbonyl groups, the mono-C₁₋₆ alkylamino groups, the di-C₁₋₆alkylamino groups, the mono-C₁₋₆ alkylaminocarbonyl groups, the di-C₁₋₆alkylaminocarbonyl groups and the C₁₋₆ alkylcarbonylamino groups areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(3b)),C₃₋₁₁ cycloalkyl groups, 3 to 11-membered non-aromatic heterocyclylgroups, C₆₋₁₄ aryl groups and 5 to 10-membered aromatic heterocyclylgroups (the C₃₋₁₁ cycloalkyl groups, the 3 to 11-membered non-aromaticheterocyclyl groups, the C₆₋₁₄ aryl groups and the 5 to 10-memberedaromatic heterocyclyl groups are unsubstituted or substituted with oneor more identical or different substituents independently selected fromthe substituent set V^(1b)),the substituent set V^(5b) consists of hydroxy groups, amino groups,carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups,phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups,halogen atoms, cyano groups, nitro groups, C₁₋₆ alkoxy groups, C₁₋₆alkylthio groups, C₁₋₆ alkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups,C₁₋₆ alkoxycarbonyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆alkylamino groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆alkylaminocarbonyl groups, C₁₋₆ alkylcarbonylamino groups, C₃₋₁₁cycloalkyl groups, 3 to 11-membered non-aromatic heterocyclyl groups,C₆₋₁₄ aryl groups and 5 to 10-membered aromatic heterocyclyl groups (theC₁₋₆ alkoxy groups, the C₁₋₆ alkylthio groups, the C₁₋₆ alkylcarbonylgroups, the C₁₋₆ alkylsulfonyl groups, the C₁₋₆ alkoxycarbonyl groups,the mono-C₁₋₆ alkylamino groups, the di-C₁₋₆ alkylamino groups, themono-C₁₋₆ alkylaminocarbonyl groups, the di-C₁₋₆ alkylaminocarbonylgroups, the C₁₋₆ alkylcarbonylamino groups, the C₃₋₁₁ cycloalkyl groups,the 3 to 11-membered non-aromatic heterocyclyl groups, the C₆₋₁₄ arylgroups and the 5 to 10-membered aromatic heterocyclyl groups areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(3b)),the substituent set V^(6b) consists of hydroxy groups, amino groups,carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups,phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups,halogen atoms, cyano groups, nitro groups, C₁₋₆ alkoxy groups, C₁₋₆alkylthio groups, C₁₋₆ alkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups,C₁₋₆ alkoxycarbonyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆alkylamino groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆alkylaminocarbonyl groups, C₁₋₆ alkylcarbonylamino groups (the C₁₋₆alkoxy groups, the C₁₋₆ alkylthio groups, the C₁₋₆ alkylcarbonyl groups,the C₁₋₆ alkylsulfonyl groups, the C₁₋₆ alkoxycarbonyl groups, themono-C₁₋₆ alkylamino groups, the di-C₁₋₆ alkylamino groups, themono-C₁₋₆ alkylaminocarbonyl groups, the di-C₁₋₆ alkylaminocarbonylgroups and the C₁₋₆ alkylcarbonylamino groups are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the substituent set V^(3b)), C₃₋₁₁cycloalkyl groups, 3 to 11-membered non-aromatic heterocyclyl groups,C₆₋₁₄ aryl groups, 5 to 10-membered aromatic heterocyclyl groups, 8 to14-membered partially saturated aromatic cyclic groups and 8 to14-membered aromatic ring-condensed alicyclic hydrocarbon groups (theC₃₋₁₁ cycloalkyl groups, the 3 to 11-membered non-aromatic heterocyclylgroups, the C₆₋₁₄ aryl groups, the 5 to 10-membered aromaticheterocyclyl groups, the 8 to 14-membered partially saturated aromaticcyclic groups and the 8 to 14-membered aromatic ring-condensed alicyclichydrocarbon groups are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(4b) and the substituent set V^(9b)), and thesubstituent set V^(8b) consists of 8 to 14-membered partially saturatedaromatic cyclic groups and 8 to 14-membered aromatic ring-condensedalicyclic hydrocarbon groups (the 8 to 14-membered partially saturatedaromatic cyclic groups and the 8 to 14-membered aromatic ring-condensedalicyclic hydrocarbon groups are unsubstituted or substituted with oneor more identical or different substituents independently selected fromthe substituent set V^(2b)),the substituent set V^(9b) consists of, mono-C₁₋₆ alkylaminosulfonylgroups, di-C₁₋₆ alkylaminosulfonyl groups, C₁₋₆ alkylsulfonylaminogroups (the mono-C₁₋₆ alkylaminosulfonyl groups, di-C₁₋₆alkylaminosulfonyl groups and C₁₋₆ alkylsulfonylamino groups areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(3b)),C₃₋₆ cycloalkoxy groups, C₃₋₆ cycloalkylamino groups, C₃₋₆cycloalkylthio groups, C₃₋₆ cycloalkylcarbonyl groups and C₃₋₆cycloalkylsulfonyl groups (the C₃₋₆ cycloalkoxy groups, the C₃₋₆cycloalkylamino groups, the C₃₋₆ cycloalkylthio groups, the C₃₋₆cycloalkylcarbonyl groups and the C₃₋₆ cycloalkylsulfonyl groupsunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(2b))], atautomer or a pharmaceutically acceptable salt of the compound or asolvate thereof.(42) The compound according to (41), which is represented by the formula(I^(b)):

[wherein the ring A^(b) is represented by the formula (II^(b)):

(wherein T^(1b) is CR^(4b)R^(5b), C(═O), C(═S), C(═NR^(17b)), a sulfuratom, S(═O) or S(═O)₂, U^(1b) is a nitrogen atom or CR^(6b), and W^(1b)is a nitrogen atom or CR^(8b)), the formula (III^(b)):

(wherein T^(2b) is CR^(4b), U^(2b) is a nitrogen atom or CR^(6b), andW^(2b) is CR^(8b)R^(9b), C(═O), C(═S), C(═NR^(17b)), NR^(10b), an oxygenatom, a sulfur atom, S(═O) or S(═O)₂ (provided that when U^(2b) isCR^(6b), W^(2b) is not C(═O))), or the formula (IV^(b)):

(wherein T^(3b) is CR^(4b)R^(5b), C(═O), C(═S), C(═NR^(17b)), a sulfuratom, S(═O) or S(═O)₂, U^(3b) is CR^(6b)R^(7b), C(═O), C(═S),C(═NR^(17b)), NR^(10b), an oxygen atom, a sulfur atom, S(═O) or S(═O)₂,and W^(3b) is CR^(8b)R^(9b), C(═O), C(═NR^(17b)), NR^(11b), an oxygenatom, a sulfur atom, S(═O) or S(═O)₂ (provided that when T^(3b) isCR^(4b)R^(5b) and U^(3b) is CR^(6b)R^(7b), W^(3b) is notCR^(8b)R^(9b))),X^(b) is a nitrogen atom or CR^(15b),Y^(b) is CR^(16b),R^(1b) is a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group or a C₁₋₆haloalkyl group, the ring B^(b) is a C₃₋₁₁ cycloalkane, a C₃₋₁₁cycloalkene, a 3 to 11-membered non-aromatic heterocycle, a C₆₋₁₄aromatic carbocycle or a 5 to 10-membered aromatic heterocycle,L^(1b) is a single bond, a C₁₋₆ alkylene group, a C₂₋₆ alkenylene groupor a C₂₋₆ alkynylene group (the C₁₋₆ alkylene group, the C₂₋₆ alkenylenegroup and the C₂₋₆ alkynylene group are unsubstituted or substitutedwith one or more identical or different substituents independentlyselected from the group consisting of halogen atoms, hydroxy groups,amino groups, cyano groups and nitro groups),L^(2b) is a single bond, a C₁₋₆ alkylene group, a C₂₋₆ alkenylene groupor a C₂₋₆ alkynylene group (the C₁₋₆ alkylene group, the C₂₋₆ alkenylenegroup and the C₂₋₆ alkynylene group are unsubstituted or substitutedwith one or more identical or different substituents independentlyselected from the group consisting of halogen atoms, hydroxy groups,amino groups, cyano groups and nitro groups),L^(3b) is a single bond or represented by any of the following formulae(V^(b)-1) to (V^(b)-20):

(wherein E^(1b) is an oxygen atom, a sulfur atom or NR^(18b)),when L^(3b) is a single bond, R^(2b) is a hydrogen atom, a halogen atom,a C₃₋₁₁ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclylgroup, a C₆₋₁₄ aryl group or a 5 to 10-membered aromatic heterocyclylgroup (the C₃₋₁₁ cycloalkyl group, the 3 to 11-membered non-aromaticheterocyclyl group, the C₆₋₁₄ aryl group and the 5 to 10-memberedaromatic heterocyclyl group are unsubstituted or substituted with one ormore identical or different substituents independently selected from thesubstituent set V^(4b)),when L^(3b) is not a single bond, R^(2b) is a hydrogen atom, a C₁₋₆alkyl group, a C₂₋₆ alkenyl group (the C₁₋₆ alkyl group and the C₂₋₆alkenyl group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(5b)), a C₃₋₁₁ cycloalkyl group, a 3 to 11-memberednon-aromatic heterocyclyl group, a C₆₋₁₄ aryl group or a 5 to10-membered aromatic heterocyclyl group (the C₃₋₁₁ cycloalkyl group, the3 to 11-membered non-aromatic heterocyclyl group, the C₆₋₁₄ aryl groupand the 5 to 10-membered aromatic heterocyclyl group are unsubstitutedor substituted with one or more identical or different substituentsindependently selected from the substituent set V^(4b)),n^(b) is 0, 1 or 2,R^(3b) is a hydroxy group, an amino group, a carboxy group, a carbamoylgroup, a sulfamoyl group, a phosphono group, a phosphonooxy group, asulfo group, a sulfoxy group, a tetrazolyl group, a halogen atom, acyano group, a nitro group, a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group,a C₃₋₁₁ cycloalkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ haloalkenylgroup, a C₁₋₆ alkoxy group, a C₁₋₆ haloalkoxy group, a C₁₋₆ alkylthiogroup, a C₁₋₆ haloalkylthio group, a C₁₋₆ alkylcarbonyl group, a C₁₋₆haloalkylcarbonyl group, a C₁₋₆ alkylsulfonyl group, a C₁₋₆haloalkylsulfonyl group, a C₁₋₆ alkoxycarbonyl group, a mono-C₁₋₆alkylamino group, a di-C₁₋₆ alkylamino group, a mono-C₁₋₆alkylaminocarbonyl group, a di-C₁₋₆ alkylaminocarbonyl group or a C₁₋₆alkylcarbonylamino group (when n^(b) is 2, R^(3b)'s may be identical ordifferent),each of R^(4b), R^(5b), R^(6b), R^(7b), R^(8b) and R^(9b) isindependently a hydrogen atom, a hydroxy group, an amino group, acarboxy group, a carbamoyl group, a tetrazolyl group, a halogen atom, acyano group, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxygroup, a C₁₋₆ alkylthio group, a C₁₋₆ alkylcarbonyl group, a C₁₋₆alkylsulfonyl group, a mono-C₁₋₆ alkylamino group, a di-C₁₋₆ alkylaminogroup (the C₁₋₆ alkyl group, the C₂₋₆ alkenyl group, the C₁₋₆ alkoxygroup, the C₁₋₆ alkylthio group, the C₁₋₆ alkylcarbonyl group, the C₁₋₆alkylsulfonyl group, the mono-C₁₋₆ alkylamino group and the di-C₁₋₆alkylamino group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(3b)), a C₁₋₆ alkoxycarbonyl group, a C₃₋₁₁ cycloalkylgroup, a 3 to 11-membered non-aromatic heterocyclyl group, a C₆₋₁₄ arylgroup or a 5 to 10-membered aromatic heterocyclyl group (the C₃₋₁₁cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclyl group,the C₆₋₁₄ aryl group and the 5 to 10-membered aromatic heterocyclylgroup are unsubstituted or substituted with one or more identical ordifferent substituents independently selected from the substituent setV^(1b)),each of R^(10b) and R^(11b) is independently a hydrogen atom, a C₁₋₆alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkylcarbonyl group, a C₁₋₆alkylsulfonyl group, a C₁₋₆ alkoxycarbonyl group, a mono-C₁₋₆alkylaminocarbonyl group, a di-C₁₋₆ alkylaminocarbonyl group (the C₁₋₆alkyl group, the C₂₋₆ alkenyl group, the C₁₋₆ alkylcarbonyl group, theC₁₋₆ alkylsulfonyl group, the C₁₋₆ alkoxycarbonyl group, the mono-C₁₋₆alkylaminocarbonyl group and the di-C₁₋₆ alkylaminocarbonyl group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(3b)), aC₃₋₁₁ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclylgroup, a C₆₋₁₄ aryl group or a 5 to 10-membered aromatic heterocyclylgroup (the C₃₋₁₁ cycloalkyl group, the 3 to 11-membered non-aromaticheterocyclyl group, the C₆₋₁₄ aryl group and the 5 to 10-memberedaromatic heterocyclyl group are unsubstituted or substituted with one ormore identical or different substituents independently selected from thesubstituent set V^(1b)),each of R^(12b), R^(13b) and R^(14b) is independently a hydrogen atom, aC₁₋₆ alkyl group or a C₁₋₆ haloalkyl group (the C₁₋₆ alkyl group and theC₁₋₆ haloalkyl group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(3b)),each of R^(15b) and R^(16b) is independently a hydrogen atom, a halogenatom, a cyano group, a carbamoyl group, a C₁₋₆ alkyl group, a C₁₋₆haloalkyl group, a C₃₋₁₁ cycloalkyl group, a C₁₋₆ alkoxy group, a C₁₋₆haloalkoxy group, a C₁₋₆ alkylthio group, a C₁₋₆ alkylcarbonyl group, aC₁₋₆ alkylsulfonyl group, a 3 to 11-membered non-aromatic heterocyclylgroup, a C₆₋₁₄ aryl group or a 5 to 10-membered aromatic heterocyclylgroup,each of R^(17b) and R^(18b) is independently a hydrogen atom, a hydroxygroup, a cyano group, a nitro group, a C₁₋₆ alkyl group or a C₁₋₆ alkoxygroup, the substituent set V^(1b) consists of hydroxy groups, aminogroups, carboxy groups, carbamoyl groups, sulfamoyl groups, phosphonogroups, phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolylgroups, halogen atoms, cyano groups, nitro groups, C₁₋₆ alkyl groups,C₁₋₆ haloalkyl groups, C₃₋₁₁ cycloalkyl groups, C₂₋₆ alkenyl groups,C₂₋₆ haloalkenyl groups, C₁₋₆ alkoxy groups, C₁₋₆ haloalkoxy groups,C₁₋₆ alkylthio groups, C₁₋₆ haloalkylthio groups, C₁₋₆ alkylcarbonylgroups, C₁₋₆ haloalkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆haloalkylsulfonyl groups, C₁₋₆ alkoxycarbonyl groups, 3 to 11-memberednon-aromatic heterocyclyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆alkylamino groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆alkylaminocarbonyl groups and C₁₋₆ alkylcarbonylamino groups,the substituent set V^(2b) consists of the groups in the substituent setV^(1b) and C₆₋₁₄ aryl groups and 5 to 10-membered aromatic heterocyclylgroups (the C₆₋₁₄ aryl groups and 5 to 10-membered aromatic heterocyclylgroups are unsubstituted or substituted with one or more identical ordifferent substituents independently selected from the substituent setV^(1b)),the substituent set V^(3b) consists of hydroxy groups, amino groups,carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups,phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups,halogen atoms, cyano groups, nitro groups, C₁₋₆ alkoxy groups, C₁₋₆haloalkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆ haloalkylthio groups,C₁₋₆ alkylcarbonyl groups, C₁₋₆ haloalkylcarbonyl groups, C₁₋₆alkylsulfonyl groups, C₁₋₆ haloalkylsulfonyl groups, C₁₋₆ alkoxycarbonylgroups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups,mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups,C₁₋₆ alkylcarbonylamino groups, C₃₋₁₁ cycloalkyl groups, 3 to11-membered non-aromatic heterocyclyl groups, C₆₋₁₄ aryl groups and 5 to10-membered aromatic heterocyclyl groups (the C₃₋₁₁ cycloalkyl groups,the 3 to 11-membered non-aromatic heterocyclyl groups, the C₆₋₁₄ arylgroups and the 5 to 10-membered aromatic heterocyclyl groups areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(1b)),the substituent set V^(4b) consists of hydroxy groups, amino groups,carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups,phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups,halogen atoms, cyano groups, nitro groups, C₁₋₆ alkyl groups, C₂₋₆alkenyl groups, C₁₋₆ alkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆alkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆ alkoxycarbonylgroups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups,mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups,C₁₋₆ alkylcarbonylamino groups (the C₁₋₆ alkyl groups, the C₂₋₆ alkenylgroups, the C₁₋₆ alkoxy groups, the C₁₋₆ alkylthio groups, the C₁₋₆alkylcarbonyl groups, the C₁₋₆ alkylsulfonyl groups, the C₁₋₆alkoxycarbonyl groups, the mono-C₁₋₆ alkylamino groups, the di-C₁₋₆alkylamino groups, the mono-C₁₋₆ alkylaminocarbonyl groups, the di-C₁₋₆alkylaminocarbonyl groups and the C₁₋₆ alkylcarbonylamino groups areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(3b)),C₃₋₁₁ cycloalkyl groups, 3 to 11-membered non-aromatic heterocyclylgroups, C₆₋₁₄ aryl groups and 5 to 10-membered aromatic heterocyclylgroups (the C₃₋₁₁ cycloalkyl groups, the 3 to 11-membered non-aromaticheterocyclyl groups, the C₆₋₁₄ aryl groups and the 5 to 10-memberedaromatic heterocyclyl groups are unsubstituted or substituted with oneor more identical or different substituents independently selected fromthe substituent set V^(1b)), andthe substituent set V^(5b) consists of hydroxy groups, amino groups,carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups,phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups,halogen atoms, cyano groups, nitro groups, C₁₋₆ alkoxy groups, C₁₋₆alkylthio groups, C₁₋₆ alkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups,C₁₋₆ alkoxycarbonyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆alkylamino groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆alkylaminocarbonyl groups, C₁₋₆ alkylcarbonylamino groups, C₃₋₁₁cycloalkyl groups, 3 to 11-membered non-aromatic heterocyclyl groups,C₆₋₁₄ aryl groups and 5 to 10-membered aromatic heterocyclyl groups (theC₁₋₆ alkoxy groups, the C₁₋₆ alkylthio groups, the C₁₋₆ alkylcarbonylgroups, the C₁₋₆ alkylsulfonyl groups, the C₁₋₆ alkoxycarbonyl groups,the mono-C₁₋₆ alkylamino groups, the di-C₁₋₆ alkylamino groups, themono-C₁₋₆ alkylaminocarbonyl groups, the di-C₁₋₆ alkylaminocarbonylgroups, the C₁₋₆ alkylcarbonylamino groups, the C₃₋₁₁ cycloalkyl groups,the 3 to 11-membered non-aromatic heterocyclyl groups, the C₆₋₁₄ arylgroups and the 5 to 10-membered aromatic heterocyclyl groups areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(3b))], atautomer or a pharmaceutically acceptable salt of the compound or asolvate thereof.(43) The compound according to (42), wherein R^(1b) is a hydrogen atom,a tautomer or a pharmaceutically acceptable salt of the compound or asolvate thereof.(44) The compound according to (42) or (43), wherein X^(b) is a nitrogenatom or CR^(15b) (wherein R^(15b) is a hydrogen atom, a halogen atom, acyano group, a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group or a C₃₋₆cycloalkyl group), andY^(b) is CR^(16b) (wherein R^(16b) is a hydrogen atom), a tautomer or apharmaceutically acceptable salt of the compound or a solvate thereof.(45) The compound according to (44), wherein X^(b) is a nitrogen atom orCR^(15b) (wherein R^(15b) is a hydrogen atom or a halogen atom), atautomer or a pharmaceutically acceptable salt of the compound or asolvate thereof.(46) The compound according to any one of (42) to (45), wherein the ringA^(b) is represented by the formula (II^(b)):

(wherein T^(1b) is CR^(4b)R^(5b), C(═O), C(═S) or S(═O)₂, U^(1b) is anitrogen atom or CR^(6b), and W^(1b) is CR^(8b)), the formula (III^(b)):

(wherein T^(2b) is CR^(4b), U^(2b) is a nitrogen atom, and W^(2b) isC(═O) or C(═S)) or the formula

(wherein T^(3b) is CR^(4b)R^(5b), U^(3b) is NR^(10b) or an oxygen atom,and W^(3b) is CR^(8b)R^(9b), C(═O) or C(═S)), a tautomer or apharmaceutically acceptable salt of the compound or a solvate thereof.(47) The compound according to any one of (42) to (45), wherein the ringA^(b) is represented by any of the following formulae (XVIII^(b)-1) to(XVIII^(b)-8):

(wherein each of E^(2b) and E^(3b) is independently an oxygen atom or asulfur atom, each of R^(4b), R^(5b), R^(6b), R^(8b) and R^(9b) isindependently a hydrogen atom, a halogen atom or a C₁₋₃ alkyl group, andR^(10b) is a hydrogen atom or a C₁₋₃ alkyl group), a tautomer or apharmaceutically acceptable salt of the compound or a solvate thereof.(48) The compound according to any one of (42) to (47), wherein L^(1b)is a single bond, L^(2b) is a single bond, a C₁₋₆ alkylene group or aC₂₋₆ alkenylene group (the C₁₋₆ alkylene group and the C₂₋₆ alkenylenegroup are unsubstituted or substituted with one or more identical ordifferent substituents independently selected from the group consistingof a halogen atoms, hydroxy groups, amino groups, cyano groups and nitrogroups), the ring B^(b) is a C₃₋₁₁ cycloalkane, a C₃₋₁₁ cycloalkene, a 3to 11-membered non-aromatic heterocycle, a C₆₋₁₄ aromatic carbocycle ora 5 to 10-membered aromatic heterocycle,n^(b) is, 0 or 1,R^(3b) is a hydroxy group, an amino group, a halogen atom, a cyanogroup, a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group, a C₃₋₆ cycloalkylgroup, a C₁₋₃ alkoxy group, a C₁₋₃ haloalkoxy group or a C₁₋₃alkylsulfonyl group,L^(3b) is a single bond, andR^(2b) is a hydrogen atom, a halogen atom, a C₃₋₁₁ cycloalkyl group, a 3to 11-membered non-aromatic heterocyclyl group, a phenyl group, anaphthyl group or a 5 to 10-membered aromatic heterocyclyl group (theC₃₋₁₁ cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclylgroup, the phenyl group, the naphthyl group and the 5 to 10-memberedaromatic heterocyclyl group are unsubstituted or substituted with one ormore identical or different substituents independently selected from thesubstituent set V^(4b)), a tautomer or a pharmaceutically acceptablesalt of the compound or a solvate thereof.(49) The compound according to any one of (42) to (47), wherein L^(1b)is a single bond or a C₁₋₃ alkylene group,L^(2b) is a single bond or a C₁₋₃ alkylene group (the C₁₋₃ alkylenegroup is unsubstituted or substituted with a cyano group or a C₁₋₃haloalkyl group),the ring B^(b) is a C₃₋₁₁ cycloalkane, a C₃₋₁₁ cycloalkene, a 3 to11-membered non-aromatic heterocycle, benzene or a 5 to 6-memberedaromatic heterocycle,n^(b) is, 0 or 1,R^(3b) is a hydroxy group, an amino group, a carboxy group, a carbamoylgroup, a tetrazolyl group, a halogen atom, a cyano group, a nitro group,a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group, a C₃₋₆ cycloalkyl group, aC₁₋₃ alkoxy group, a C₁₋₃ haloalkoxy group ora C₁₋₃ alkylsulfonyl group,L^(3b) is a single bond, andR^(2b) is a hydrogen atom, a halogen atom, a C₃₋₆ cycloalkyl group, a 4to 7-membered non-aromatic heterocyclyl group, a phenyl group or a 5 to6-membered aromatic heterocyclyl group (the C₃₋₆ cycloalkyl group, the 4to 7-membered non-aromatic heterocyclyl group, the phenyl group and the5 to 6-membered aromatic heterocyclyl group are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the substituent set V^(4b)), a tautomer or apharmaceutically acceptable salt of the compound or a solvate thereof.(50) The compound according to (48), wherein the ring B^(b) is a C₃₋₁₁cycloalkane or a 4 to 7-membered non-aromatic heterocycle,n^(b) is 0 or 1, andR^(3b) is a hydroxy group, a C₁₋₃ alkyl group or a C₁₋₃ alkoxy group, atautomer or a pharmaceutically acceptable salt of the compound or asolvate thereof.(51) The compound according to (48) or (50), wherein L^(2b) is a singlebond, a C₁₋₆ alkylene group, a C₂₋₆ alkenylene group or a C₁₋₆haloalkylene group (the C₁₋₆ alkylene group, the C₂₋₆ alkenylene groupand the C₁₋₆ haloalkylene group are unsubstituted or substituted withone or two identical or different substituents independently selectedfrom the group consisting of hydroxy groups and cyano groups), atautomer or a pharmaceutically acceptable salt of the compound or asolvate thereof.(52) The compound according to any one of (48), (50) and (51), whereinR^(2b) is a hydrogen atom, a C₃₋₆ cycloalkyl group, a 4 to 7-memberednon-aromatic heterocyclyl group, a phenyl group or a 5 to 10-memberedaromatic heterocyclyl group (the 4 to 7-membered non-aromaticheterocyclyl group, the phenyl group and the 5 to 10-membered aromaticheterocyclyl group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thegroup consisting of hydroxy groups, amino groups, carbamoyl groups,sulfamoyl groups, halogen atoms, cyano groups, nitro groups, C₁₋₆ alkylgroups, C₁₋₆ alkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆ alkylsulfonylgroups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups, C₁₋₆alkoxycarbonyl groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆alkylaminocarbonyl groups, C₁₋₆ alkylcarbonylamino groups (the C₁₋₆alkyl groups, the C₁₋₆ alkoxy groups, the C₁₋₆ alkylthio groups, theC₁₋₆ alkylsulfonyl groups, the mono-C₁₋₆ alkylamino groups, the di-C₁₋₆alkylamino groups, the C₁₋₆ alkoxycarbonyl groups, the mono-C₁₋₆alkylaminocarbonyl groups, the di-C₁₋₆ alkylaminocarbonyl groups and theC₁₋₆ alkylcarbonylamino groups are unsubstituted or substituted with oneor more identical or different halogen atoms independently selected fromthe group consisting of fluorine atoms, chlorine atoms, bromine atomsand iodine atoms or with a hydroxy group or a cyano group), C₃₋₆cycloalkyl groups, 4 to 7-membered non-aromatic heterocyclyl groups,phenyl groups and 5 to 6-membered aromatic heterocyclyl groups), atautomer or a pharmaceutically acceptable salt of the compound or asolvate thereof.(53) The compound according to (52), wherein R^(2b) is a hydrogen atom,a 4 to 7-membered non-aromatic heterocyclyl group, a phenyl group or a 5to 10-membered aromatic heterocyclyl group (the 4 to 7-memberednon-aromatic heterocyclyl group, the phenyl group and the 5 to10-membered aromatic heterocyclyl group are unsubstituted or substitutedwith one or two identical or different substituents independentlyselected from the group consisting of hydroxy groups, halogen atoms,cyano groups, nitro groups, C₁₋₃ alkyl groups (the C₁₋₃ alkyl groups areunsubstituted or substituted with a cyano group), C₁₋₃ haloalkyl groupsand C₁₋₆ alkoxycarbonyl groups), a tautomer or a pharmaceuticallyacceptable salt of the compound or a solvate thereof.(54) The compound according to any one of (48) and (50) to (53), whereinL^(2b) is a C₁₋₆ alkylene group, a C₂₋₃ alkenylene group (the C₁₋₆alkylene group and the C₂₋₃ alkenylene group are unsubstituted orsubstituted with a cyano group) or C₁₋₆ haloalkylene group, and R^(2b)is, a hydrogen atom, a tautomer or a pharmaceutically acceptable salt ofthe compound or a solvate thereof.(55) The compound according to any one of (42) to (47), wherein L^(1b)is a single bond, L^(2b) is a single bond, a C₁₋₆ alkylene group or aC₂₋₆ alkenylene group (the C₁₋₆ alkylene group and the C₂₋₆ alkenylenegroup are unsubstituted or substituted with one or more identical ordifferent substituents independently selected from the group consistingof halogen atoms, hydroxy groups, amino groups, cyano groups and nitrogroups), the ring B^(b) is a C₃₋₁₁ cycloalkane, a C₃₋₁₁ cycloalkene, a 3to 11-membered non-aromatic heterocyclyl group, a C₆₋₁₄ aryl group or a5 to 10-membered aromatic heterocycle,n^(b) is 0 or 1,R^(3b) is a hydroxy group, an amino group, a halogen atom, a cyanogroup, a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group, a C₃₋₆ cycloalkylgroup, a C₁₋₃ alkoxy group or a C₁₋₃ haloalkoxy group,L^(3b) is represented by any of the following formulae (VI^(b)-1) to(VI^(b)-11):

(wherein E^(1b) is an oxygen atom or a sulfur atom, each of R^(12b) andR^(13b) is independently a hydrogen atom, a C₁₋₆ alkyl group or a C₁₋₆haloalkyl group (the C₁₋₆ alkyl group and the C₁₋₆ haloalkyl group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the group consisting of halogenatoms, cyano groups, hydroxy group, C₁₋₆ alkoxy groups, C₁₋₆ alkylthiogroups, C₁₋₆ alkylsulfonyl groups, C₃₋₆ cycloalkyl groups, 4 to7-membered non-aromatic heterocyclyl groups, phenyl groups and 5 to6-membered aromatic heterocyclyl groups (the phenyl groups and the 5 to6-membered aromatic heterocyclyl groups are unsubstituted or substitutedwith a substituent selected from the group consisting of a halogen atom,a cyano group, a C₁₋₃ alkyl group and a C₁₋₃ haloalkyl group))), andR^(2b) is a hydrogen atom, a C₁₋₆ alkyl group (the C₁₋₆ alkyl group isunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(5b)), aC₃₋₁₁ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclylgroup, a phenyl group, a naphthyl group or a 5 to 10-membered aromaticheterocyclyl group (the C₃₋₁₁ cycloalkyl group, the 3 to 11-memberednon-aromatic heterocyclyl group, the phenyl group, the naphthyl groupand the 5 to 10-membered aromatic heterocyclyl group are unsubstitutedor substituted with one or more identical or different substituentsindependently selected from the substituent set V^(4b)), a tautomer or apharmaceutically acceptable salt of the compound or a solvate thereof.(56) The compound according to any one of (42) to (47), wherein L^(1b)is a single bond or a C₁₋₃ alkylene group,L^(2b) is a single bond or a C₁₋₃ alkylene group (the C₁₋₃ alkylenegroup is unsubstituted or substituted with a cyano group or a C₁₋₃haloalkyl group),the ring B^(b) is a C₃₋₁₁ cycloalkane, a C₃₋₁₁ cycloalkene, a 3 to11-membered non-aromatic heterocycle, benzene or a 5 to 6-memberedaromatic heterocycle,n^(b) is 0 or 1,R^(3b) is a hydroxy group, an amino group, a carbamoyl group, a halogenatom, a cyano group, a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group, a C₃₋₆cycloalkyl group, a C₁₋₃ alkoxy group, a C₁₋₃ haloalkoxy group or a C₁₋₃alkylsulfonyl group,L^(3b) is represented by any of the following formulae (VI^(b)-1) to(VI^(b)-11):

(wherein E^(1b) is an oxygen atom, each of R^(12b) and R^(13b) isindependently a hydrogen atom, a C₁₋₆ alkyl group or a C₁₋₆ haloalkylgroup), andR^(2b) is a hydrogen atom, a C₁₋₆ alkyl group (the C₁₋₆ alkyl group isunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(5b)), aC₃₋₆ cycloalkyl group, a 4 to 7-membered non-aromatic heterocyclylgroup, a phenyl group or a 5 to 6-membered aromatic heterocyclyl group(the C₃₋₆ cycloalkyl group, the 4 to 7-membered non-aromaticheterocyclyl group, the phenyl group and the 5 to 6-membered aromaticheterocyclyl group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(1b)), a tautomer or a pharmaceutically acceptablesalt of the compound or a solvate thereof.(57) The compound according to (55), wherein the ring B^(b) is a C₃₋₁₁cycloalkane or a 4 to 7-membered non-aromatic heterocycle,L^(3b) is represented by any of the following formulae (XIX^(b)-1) to(XIX^(b)-7):

(wherein E^(1b) is an oxygen atom, and R^(12b) is a hydrogen atom, aC₁₋₆ alkyl group (the C₁₋₆ alkyl group is unsubstituted or substitutedwith one or more identical or different substituents independentlyselected from the group consisting of cyano groups, hydroxy groups, C₁₋₃alkoxy groups, C₃₋₆ cycloalkyl groups and phenyl groups) or a C₁₋₆haloalkyl group), andR^(2b) is a hydrogen atom, a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group(the C₁₋₆ alkyl group and the C₁₋₆ haloalkyl group are unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of hydroxy groups,cyano groups, C₁₋₃ alkoxy groups, C₁₋₃ alkylthio groups, C₁₋₃alkylsulfonyl groups, C₃₋₆ cycloalkyl groups, 4 to 7-memberednon-aromatic heterocyclyl groups, phenyl groups and 5 to 6-memberedaromatic heterocyclyl groups (the C₃₋₆ cycloalkyl groups, the 4 to7-membered non-aromatic heterocyclyl groups, the phenyl groups and the 5to 6-membered aromatic heterocyclyl groups are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the group consisting of halogen atoms,hydroxy groups, cyano groups, C₁₋₆ alkoxy groups, C₁₋₆ haloalkoxy groupsand C₁₋₆ alkoxycarbonyl groups)), a C₃₋₆ cycloalkyl group, a 4 to7-membered non-aromatic heterocyclyl group, a phenyl group or a 5 to6-membered aromatic heterocyclyl group (the C₃₋₆ cycloalkyl group, the 4to 7-membered non-aromatic heterocyclyl group, the phenyl group and the5 to 6-membered aromatic heterocyclyl group are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the group consisting of halogen atoms,hydroxy groups, cyano groups, C₁₋₆ alkyl groups, C₁₋₆ haloalkyl groups,C₁₋₆ alkoxy groups, C₁₋₆ haloalkoxy groups and C₁₋₆ alkoxycarbonylgroups), a tautomer or a pharmaceutically acceptable salt of thecompound or a solvate thereof.(58) The compound according to (55) or (57), wherein L^(3b) isrepresented by any of the following formulae (XX^(b)-1) to (XX^(b)-4):

(wherein E^(1b) is an oxygen atom, and R^(12b) is a hydrogen atom, aC₁₋₃ alkyl group (the C₁₋₃ alkyl group is unsubstituted or substitutedwith a substituent selected from the group consisting of a cyano group,a hydroxy group, a C₁₋₃ alkoxy group, a C₃₋₆ cycloalkyl group and aphenyl group) or C₁₋₃ haloalkyl group)), andR^(2b) is a hydrogen atom, a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group(the C₁₋₃ alkyl group and the C₁₋₃ haloalkyl group are unsubstituted orsubstituted with one or two identical or different substituent selectedfrom the group consisting of hydroxy groups, cyano groups, C₁₋₃ alkoxygroups, C₃₋₆ cycloalkyl groups, 4 to 7-membered non-aromaticheterocyclyl groups, phenyl groups and 5 to 6-membered aromaticheterocyclyl groups (the C₃₋₆ cycloalkyl groups, the 4 to 7-memberednon-aromatic heterocyclyl groups, the phenyl groups and the 5 to6-membered aromatic heterocyclyl groups are unsubstituted or substitutedwith a hydroxy group or a halogen atom)), a C₃₋₆ cycloalkyl group, a 4to 7-membered non-aromatic heterocyclyl group, a phenyl group or a 5 to6-membered aromatic heterocyclyl group (the C₃₋₆ cycloalkyl group, the 4to 7-membered non-aromatic heterocyclyl group, the phenyl group and the5 to 6-membered aromatic heterocyclyl group are unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of hydroxy groups,halogen atoms, cyano groups, C₁₋₆ alkyl groups, C₁₋₃ haloalkyl groupsand C₁₋₆ alkoxycarbonyl groups), a tautomer or a pharmaceuticallyacceptable salt of the compound or a solvate thereof.(59) The compound according to any one of (48) to (53) or (55) to (58),wherein L^(2b) is a single bond or a C₁₋₃ alkylene group, a tautomer ora pharmaceutically acceptable salt of the compound or a solvate thereof.(60) The compound according to any one of (44) to (59), wherein X^(b) isa nitrogen atom or CR^(15b) (wherein R^(15b) is a hydrogen atom), andY^(b) is CR^(16b) (wherein R^(16b) is a hydrogen atom), a tautomer or apharmaceutically acceptable salt of the compound or a solvate thereof.(61) The compound according to any one of (46) to (60), wherein the ringA^(b) is represented by any of the following formulae (VII^(b)-1) to(VII^(b)-7):

(wherein E^(2b) is an oxygen atom, and each of R^(4b), R^(5b), R^(6b),R^(8b), R^(9b) and R^(10b) is independently a hydrogen atom or a C₁₋₃alkyl group), a tautomer or a pharmaceutically acceptable salt of thecompound or a solvate thereof.(62) The compound according to any one of (46) to (60), wherein the ringA^(b) is represented by any of the following formulae (XXXIII^(b)-1) to(XXXIII^(b)-3):

(wherein E^(2b) is an oxygen atom, and each of R^(4b), R^(5b), R^(8b),R^(9b) and R^(10b) are hydrogen atoms, and R^(6b) is a hydrogen atom, ahalogen atom or a C₁₋₃ alkyl group), a tautomer or a pharmaceuticallyacceptable salt of the compound or a solvate thereof.(63) The compound according to any one of (49), (60) and (61), whereinL^(1b) is a single bond,L^(2b) is a C₁₋₃ alkylene group,the ring B^(b) is a C₄₋₇ cycloalkane or a 4 to 7-membered non-aromaticheterocycle,n^(b) is 0 or 1,R^(3b) is a C₁₋₃ alkyl group,L^(3b) is a single bond, andR^(2b) is a hydrogen atom or a phenyl group (the phenyl group isunsubstituted or substituted with one or more identical or differenthalogen atoms independently selected from the group consisting offluorine atoms, chlorine atoms, bromine atoms and iodine atoms), atautomer or a pharmaceutically acceptable salt of the compound or asolvate thereof.(64) The compound according to any one of (49), (60) and (61), whereinL^(1b) is a single bond,L^(2b) is a single bond,the ring B^(b) is a C₄₋₇ cycloalkane or a 4 to 7-membered non-aromaticheterocycle,n^(b) is 0,L^(3b) is a single bond, andR^(2b) is a hydrogen atom, a tautomer or a pharmaceutically acceptablesalt of the compound or a solvate thereof.(65) The compound according to any one of (56), (60) and (61), whereinL^(1b) is a single bond,L^(2b) is a single bond,the ring B^(b) is a C₄₋₇ cycloalkane or a 4 to 7-membered non-aromaticheterocycle,n^(b) is 0 or 1,R^(3b) is a C₁₋₃ alkyl group,L^(3b) is represented by any of the following formula (VIII^(b)-1) or(VIII^(b)-2):

andR^(2b) is a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is unsubstituted orsubstituted with a cyano group or a C₃₋₆ cycloalkyl group) or a C₁₋₃haloalkyl group, a tautomer or a pharmaceutically acceptable salt of thecompound or a solvate thereof.(66) The compound according to any one of (42) to (65), wherein the ringB^(b) is cyclohexane or piperidine, a tautomer or a pharmaceuticallyacceptable salt of the compound or a solvate thereof.(67) The compound according to any one of (42) to (62), wherein the ringB^(b) is a 4 to 7-membered non-aromatic heterocycle, a tautomer or apharmaceutically acceptable salt of the compound or a solvate thereof.(68) The compound according to (41), wherein X^(b) is a nitrogen atom orCR^(15b) (wherein R^(15b) is a hydrogen atom or a halogen atom),Y^(b) is CR^(16b)(wherein R^(16b) is a hydrogen atom),R^(1b) is a hydrogen atom,the ring A^(b) is represented by any of the following formulae(XVIII^(b)-1) to (XVIII^(b)-8):

(wherein each of E^(2b) and E^(3b) is independently an oxygen atom or asulfur atom, each of R^(4b), R^(5b), R^(6b), R^(8b) and R^(9b) isindependently a hydrogen atom, a halogen atom or a C₁₋₃ alkyl group, andR^(10b) is a hydrogen atom, a C₁₋₆ alkyl group (the C₁₋₆ alkyl group isunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(3b)), aC₃₋₁₁ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclylgroup, a C₆₋₁₄ aryl group or a 5 to 10-membered aromatic heterocyclylgroup (the C₃₋₁₁ cycloalkyl group, the 3 to 11-membered non-aromaticheterocyclyl group, the C₆₋₁₄ aryl group and the 5 to 10-memberedaromatic heterocyclyl group are unsubstituted or substituted with one ormore identical or different substituents independently selected from thesubstituent set V^(1b))),the ring B^(b) is a C₃₋₁₁ cycloalkane, a 3 to 11-membered non-aromaticheterocycle, a C₆₋₁₄ aromatic carbocycle or a 5 to 10-membered aromaticheterocycle,L^(1b) is single bond or a C₁₋₃ alkylene group,L^(2b) is a single bond, a C₁₋₆ alkylene group or a C₂₋₆ alkenylenegroup (the C₁₋₆ alkylene group and the C₂₋₆ alkenylene group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the group consisting of halogenatoms, hydroxy groups, amino groups, cyano groups and nitro groups),n^(b) is 0 or 1,R^(3b) is a hydroxy group, an amino group, a carboxy group, a carbamoylgroup, a tetrazolyl group, a halogen atom, a cyano group, a nitro group,a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group, a C₃₋₆ cycloalkyl group, aC₁₋₃ alkoxy group, a C₁₋₃ haloalkoxy group or a C₁₋₃ alkylsulfonylgroup,L^(3b) is a single bond or represented by any of the following formulae(XXII^(b)-1) to (XXII^(b)-15):

(wherein E^(1b) is an oxygen atom or a sulfur atom, and each of R^(12b)and R^(13b) is independently a hydrogen atom, a C₁₋₆ alkyl group or aC₁₋₆ haloalkyl group (the C₁₋₆ alkyl group and the C₁₋₆ haloalkyl groupare unsubstituted or substituted with one or more identical or differentsubstituents independently selected from the group consisting of halogenatoms, cyano groups, hydroxy groups, C₁₋₆ alkoxy groups, C₁₋₆ alkylthiogroups, C₁₋₆ alkylsulfonyl groups, C₃₋₆ cycloalkyl groups, 4 to7-membered non-aromatic heterocyclyl groups, phenyl groups and 5 to6-membered aromatic heterocyclyl groups (the phenyl groups and 5 to6-membered aromatic heterocyclyl groups are unsubstituted or substitutedwith a substituent selected from the group consisting of a halogen atom,a cyano group, a C₁₋₃ alkyl group and a C₁₋₃ haloalkyl group))), whenL^(3b) is a single bond, R^(2b) is a hydrogen atom, a halogen atom, aC₃₋₁₁ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclylgroup, a phenyl group, a naphthyl group, a 5 to 10-membered aromaticheterocyclyl group, a 8 to 11-membered partially saturated aromaticcyclic group or a 8 to 11-membered aromatic ring-condensed alicyclichydrocarbon group (the C₃₋₁₁ cycloalkyl group, the 3 to 11-memberednon-aromatic heterocyclyl group, the phenyl group, the naphthyl group,the 5 to 10-membered aromatic heterocyclyl group, the 8 to 11-memberedpartially saturated aromatic cyclic group and the 8 to 11-memberedaromatic ring-condensed alicyclic hydrocarbon group are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the substituent set V^(4b) and thesubstituent set V^(9b)),when L^(3b) is not a single bond, R^(2b) is a hydrogen atom, a C₁₋₆alkyl group, a C₂₋₆ alkenyl group (the C₁₋₆ alkyl group and the C₂₋₆alkenyl group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(6b) and the substituent set V^(9b)), a C₃₋₁₁cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclyl group, aC₆₋₁₄ aryl group, a 5 to 10-membered aromatic heterocyclyl group, a 8 to11-membered partially saturated aromatic cyclic group or a 8 to11-membered aromatic ring-condensed alicyclic hydrocarbon group (theC₃₋₁₁ cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclylgroup, the C₆₋₁₄ aryl group, the 5 to 10-membered aromatic heterocyclylgroup, the 8 to 11-membered partially saturated aromatic cyclic group orthe 8 to 11-membered aromatic ring-condensed alicyclic hydrocarbon groupare unsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(4b) andthe substituent set V^(9b)), a tautomer or a pharmaceutically acceptablesalt of the compound or a solvate thereof.(69) The compound according to (41) or (68), wherein the ring A^(b) isrepresented by any of the following formulae (XXI^(b)-1) to (XXI^(b)-4):

(wherein each of E^(2b) and E^(3b) is independently an oxygen atom or asulfur atom, R^(4b), R^(5b), R^(8b) and R^(9b) are hydrogen atoms,R^(6b) is a hydrogen atom, a halogen atom or a C₁₋₃ alkyl group, andR^(10b) is a hydrogen atom, a C₁₋₆ alkyl group (the C₁₋₆ alkyl group isunsubstituted or substituted with one or two identical or differentsubstituents independently selected from the group consisting of cyanogroups, hydroxy groups, C₁₋₃ alkoxy groups, C₁₋₃ alkylthio groups,mono-C₁₋₃ alkylamino groups, di-C₁₋₃ alkylamino groups, mono-C₁₋₃alkylaminocarbonyl groups, di-C₁₋₃ alkylaminocarbonyl groups, C₃₋₆cycloalkyl groups, 4 to 7-membered non-aromatic heterocyclyl groups,phenyl groups and 5 to 6-membered aromatic heterocyclyl groups (thephenyl groups and the 5 to 6-membered aromatic heterocyclyl groups areunsubstituted or substituted with one or two identical or differentsubstituents independently selected from the group consisting of halogenatoms, C₁₋₃ alkyl groups and C₁₋₃ haloalkyl groups)), a C₁₋₆ haloalkylgroup, a C₃₋₆ cycloalkyl group or a 4 to 7-membered non-aromaticheterocyclyl group), a tautomer or a pharmaceutically acceptable salt ofthe compound or a solvate thereof.(70) The compound according to any one of (41), (68) and (69), whereinthe ring A^(b) is represented by the following formulae (XXIX^(b)-1) or(XXIX^(b)-2):

(wherein E^(2b) and E^(3b) are oxygen atoms, R^(6b) is a hydrogen atom,a halogen atom or a C₁₋₃ alkyl group, R^(8b) is a hydrogen atom, andR^(10b) is a hydrogen atom, a C₁₋₆ alkyl group (the C₁₋₆ alkyl group isunsubstituted or substituted with one or two identical or differentsubstituents independently selected from the group consisting of cyanogroups, hydroxy groups, C₁₋₃ alkoxy groups, C₁₋₃ alkylthio groups,di-C₁₋₃ alkylamino groups, C₃₋₆ cycloalkyl groups and 4 to 7-memberednon-aromatic heterocyclyl groups), a C₁₋₆ haloalkyl group, a C₃₋₆cycloalkyl group or a 4 to 7-membered non-aromatic heterocyclyl group, atautomer or a pharmaceutically acceptable salt of the compound or asolvate thereof.(71) The compound according to any one of (41) and (68) to (71), whereinL^(1b) is a single bond,L^(2b) is a single bond, a C₁₋₆ alkylene group, a C₂₋₆ alkenylene groupor a C₁₋₆ haloalkylene group (the C₁₋₆ alkylene group, the C₂₋₆alkenylene group and the C₁₋₆ haloalkylene group are unsubstituted orsubstituted with a hydroxy group or a cyano group),the ring B^(b) is a C₃₋₁₁ cycloalkane or a 4 to 7-membered non-aromaticheterocycle,n^(b) is 0 or 1, andR^(3b) is a hydroxy group, a C₁₋₃ alkyl group or a C₁₋₃ alkoxy group, atautomer or a pharmaceutically acceptable salt of the compound or asolvate thereof.(72) The compound according to any one of (41) and (68) to (70), whereinL^(3b) is a single bond, andR^(2b) is a hydrogen atom, a 4 to 7-membered non-aromatic heterocyclylgroup, a phenyl group, a 5 to 10-membered aromatic heterocyclyl group ora 8 to 11-membered partially saturated aromatic cyclic group (the 4 to7-membered non-aromatic heterocyclyl group, the phenyl group, the 5 to10-membered aromatic heterocyclyl group and the 8 to 11-memberedpartially saturated aromatic cyclic group are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the group consisting of hydroxy groups,amino groups, carbamoyl groups, sulfamoyl groups, halogen atoms, cyanogroups, nitro groups, C₁₋₆ alkyl groups (the C₁₋₆ alkyl groups areunsubstituted or substituted with a cyano group), C₁₋₆ haloalkyl groups,C₃₋₁₁ cycloalkyl groups, C₁₋₆ alkoxy groups, C₁₋₆ haloalkoxy groups,C₁₋₆ alkylthio groups, C₁₋₆ haloalkylthio groups, C₁₋₆ alkylsulfonylgroups, C₁₋₆ haloalkylsulfonyl groups, C₁₋₆ alkoxycarbonyl groups, 4 to7-membered non-aromatic heterocyclyl groups, mono-C₁₋₆ alkylaminogroups, di-C₁₋₆ alkylamino groups, phenyl groups, 5 to 6-memberedaromatic heterocyclyl groups, mono-C₁₋₆ alkylaminosulfonyl groups anddi-C₁₋₆ alkylaminosulfonyl groups), a tautomer or a pharmaceuticallyacceptable salt of the compound or a solvate thereof.(73) The compound according to (72), wherein R^(2b) is a hydrogen atom,a phenyl group, a 5 to 10-membered aromatic heterocyclyl group or a 8 to11-membered partially saturated aromatic cyclic group (the phenyl group,the 5 to 10-membered aromatic heterocyclyl group and the 8 to11-membered partially saturated aromatic cyclic group are unsubstitutedor substituted with one, two or three identical or differentsubstituents independently selected from the group consisting of halogenatoms, cyano groups, nitro groups, C₁₋₃ alkyl groups, C₁₋₃ haloalkylgroups and C₁₋₆ alkoxycarbonyl groups), a tautomer or a pharmaceuticallyacceptable salt of the compound or a solvate thereof.(74) The compound according to (72), wherein R^(2b) is a 4 to 7-memberednon-aromatic heterocyclyl group (the 4 to 7-membered non-aromaticheterocyclyl group is unsubstituted or substituted with one or twoidentical or different substituents independently selected from thegroup consisting of hydroxy groups, halogen atoms, cyano groups, C₁₋₃alkyl groups (the C₁₋₃ alkyl groups are unsubstituted or substitutedwith a cyano group) and C₁₋₃ haloalkyl groups), a tautomer or apharmaceutically acceptable salt of the compound or a solvate thereof.(75) The compound according to any one of (41) and (68) to (71), whereinL^(3b) is represented by any of the following formulae (XIX^(b)-1) to(XIX^(b)-7):

(wherein E^(1b) is an oxygen atom, and R^(12b) is a hydrogen atom or aC₁₋₆ alkyl group (the C₁₋₆ alkyl group is unsubstituted or substitutedwith one or more identical or different substituents independentlyselected from the group consisting of halogen atoms, cyano groups,hydroxy groups, C₁₋₃ alkoxy groups, C₃₋₆ cycloalkyl groups, 4 to7-membered non-aromatic heterocyclyl groups, phenyl groups and 5 to6-membered aromatic heterocyclyl groups)), andR^(2b) is a hydrogen atom, a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group(the C₁₋₆ alkyl group and the C₁₋₆ haloalkyl group are unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of cyano groups,hydroxy groups, C₁₋₆ alkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆alkylsulfonyl groups, C₃₋₆ cycloalkyl groups, 4 to 7-memberednon-aromatic heterocyclyl groups, phenyl groups and 5 to 6-memberedaromatic heterocyclyl groups (the C₃₋₆ cycloalkyl groups, the 4 to7-membered non-aromatic heterocyclyl groups, the phenyl groups and the 5to 6-membered aromatic heterocyclyl groups are unsubstituted orsubstituted with one, two or three identical or different substituentsindependently selected from the group consisting of the substituent setV^(2b), mono-C₁₋₆ alkylaminosulfonyl groups and di-C₁₋₆alkylaminosulfonyl groups)), a C₃₋₆ cycloalkyl group, a 4 to 7-memberednon-aromatic heterocyclyl group, a phenyl group, a 5 to 6-memberedaromatic heterocyclyl group or a 8 to 11-membered partially saturatedaromatic cyclic group (the C₃₋₆ cycloalkyl group, the 4 to 7-memberednon-aromatic heterocyclyl group, the phenyl group, the 5 to 6-memberedaromatic heterocyclyl group and the 8 to 11-membered partially saturatedaromatic cyclic group are unsubstituted or substituted with one, two orthree identical or different substituents independently selected fromthe group consisting of the substituent set V^(2b), mono-C₁₋₆alkylaminosulfonyl groups and di-C₁₋₆ alkylaminosulfonyl groups), atautomer or a pharmaceutically acceptable salt of the compound or asolvate thereof.(76) The compound according to (75), wherein L^(3b) is represented byany of the following formulae (XXXI^(b)-1) to (XXXI^(b)-5):

(wherein E^(1b) is an oxygen atom, and R^(12b) is a hydrogen atom, aC₁₋₃ alkyl group (the C₁₋₃ alkyl group is unsubstituted or substitutedwith a substituent selected from the group consisting of a cyano group,a hydroxy group, a C₁₋₃ alkoxy group, a C₃₋₆ cycloalkyl group and aphenyl group) or C₁₋₃ haloalkyl group), andR^(2b) is a hydrogen atom, a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group(the C₁₋₆ alkyl group and the C₁₋₆ haloalkyl group are unsubstituted orsubstituted with one or two identical or different substituent selectedfrom the group consisting of hydroxy groups, cyano groups, C₁₋₃ alkoxygroups, C₃₋₆ cycloalkyl groups, 4 to 7-membered non-aromaticheterocyclyl groups, phenyl groups and 5 to 6-membered aromaticheterocyclyl groups (the C₃₋₆ cycloalkyl groups, the 4 to 7-memberednon-aromatic heterocyclyl groups, the phenyl groups and the 5 to6-membered aromatic heterocyclyl groups are unsubstituted or substitutedwith a hydroxy group or a halogen atom)), a C₃₋₆ cycloalkyl group, a 4to 7-membered non-aromatic heterocyclyl group, a phenyl group or a 5 to6-membered aromatic heterocyclyl group (the C₃₋₆ cycloalkyl group, the 4to 7-membered non-aromatic heterocyclyl group, the phenyl group and the5 to 6-membered aromatic heterocyclyl group are unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of hydroxy groups,halogen atoms, cyano groups, C₁₋₃ alkyl groups, C₁₋₃ haloalkyl groupsand C₁₋₆ alkoxycarbonyl groups), a tautomer or a pharmaceuticallyacceptable salt of the compound or a solvate thereof.(77) The compound according to (75), wherein L^(3b) is represented bythe formula

(wherein R^(12b) is a hydrogen atom, a C₁₋₃ alkyl group (the C₁₋₃ alkylgroup is unsubstituted or substituted with a substituent selected fromthe group consisting of a cyano group, a hydroxy group, a C₁₋₃ alkoxygroup, a C₃₋₆ cycloalkyl group and a phenyl group) or a C₁₋₃ haloalkylgroup), andR^(2b) is a hydrogen atom, a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group(the C₁₋₃ alkyl group and the C₁₋₃ haloalkyl group are unsubstituted orsubstituted with one or two identical or different substituent selectedfrom the group consisting of hydroxy groups, cyano groups, C₁₋₃ alkoxygroups, C₃₋₆ cycloalkyl groups (the C₃₋₆ cycloalkyl groups areunsubstituted or substituted with a hydroxy groups), 4 to 7-memberednon-aromatic heterocyclyl groups, phenyl groups and 5 to 6-memberedaromatic heterocyclyl groups), a C₃₋₆ cycloalkyl group or a 4 to7-membered non-aromatic heterocyclyl group (the C₃₋₆ cycloalkyl groupand the 4 to 7-membered non-aromatic heterocyclyl group areunsubstituted or substituted with one or two identical or differentsubstituents independently selected from the group consisting of C₁₋₃alkyl groups, C₁₋₃ haloalkyl groups and C₁₋₆ alkoxycarbonyl groups), atautomer or a pharmaceutically acceptable salt of the compound or asolvate thereof.(78) The compound according to any one of (41) or (68) to (77), whereinL^(2b) is a single bond or a C₁₋₃ alkylene group, and the ring B^(b) iscyclohexane or piperidine, a tautomer or a pharmaceutically acceptablesalt of the compound or a solvate thereof.(79) The compound according to any one of (41) to (78), wherein n^(b) is0 or 1, and R^(3b) is a C₁₋₃ alkyl group, a tautomer or apharmaceutically acceptable salt of the compound or a solvate thereof.(80) A JAK inhibitor containing the compound as defined in any one of(1) to (79), a tautomer or a pharmaceutically acceptable salt of thecompound or a solvate thereof, as an active ingredient.(81) A preventive, therapeutic or improving agent for diseases againstwhich inhibition of JAK is effective, which contains the JAK inhibitoras defined in (80).(82) A therapeutic agent for articular rheumatism, which contains theJAK inhibitor as defined in (80).(83) Medicament containing the compound as defined in any one of (1) to(79), a tautomer or a pharmaceutically acceptable salt of the compoundor a solvate thereof, as an active ingredient.

The present invention has made it possible to provide novel tricyclicpyrimidine compounds and tricyclic pyridine compounds which haveexcellent JAK inhibitory action and are especially useful for preventionand treatment of autoimmune diseases, inflammatory diseases and allergicdiseases.

Now, the present invention will be described in further detail.

In the present invention, “n-” denotes normal, “i-” denotes iso, “s-” or“sec” denotes secondary, “t-” or “tert-” denotes tertiary, “c-” denotescyclo, “o-” denotes ortho, “m-” denotes meta, “p-” denotes para, “cis-”denotes a cis isomer, “trans-” denotes a trans isomer, “(E)-” denotes aE isomer, “(Z)-” denotes a Z isomer, “rac” and “racemate” denotesracemate, “diastereomixture” denotes a mixture of diastereomers, “Ph”denotes phenyl, “Py” denotes pyridyl, “Me” denotes methyl, “Et” denotesethyl, “Pr” denotes propyl, “Bu” denotes butyl, “Boc” denotestertiary-butoxycarbonyl, “Cbz” denotes benzyloxycarbonyl, “Ms” denotesmethanesulfonyl, “Tf” denotes trifluoromethanesulfonyl, “Ts” denotesp-toluenesulfonyl, “SEM” denotes [2-(trimethylsilyl)ethoxy]methyl,“TIPS” denotes triisopropylsilyl, “TBDPS” denotestertiary-butyldiphenylsilyl, and “TBS” denotestertiary-butyldimethylsilyl.

First, the terms used herein for description of chemical structures willbe explained.

A “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom oran iodine atom.

A “C₁₋₃ alkyl group” is a methyl group, an ethyl group, a propyl groupor an isopropyl group.

A “C₁₋₆ alkyl group” is a linear or branched alkyl group containing oneto six carbon atoms and may, for example, be a methyl group, an ethylgroup, a n-propyl group, an isopropyl group, a n-butyl group, anisobutyl group, a t-butyl group, a n-pentyl group, n-hexyl group or thelike.

A “C₁₋₃ haloalkyl group” is a group derived from the above-mentionedC₁₋₃ alkyl group by replacing one or more hydrogen atom(s) at arbitraryposition(s) by one or more identical or different halogen atoms selectedfrom the group consisting of fluorine atoms, chlorine atoms, bromineatoms and iodine atoms.

A “C₁₋₆ haloalkyl group” is a group derived from the above-mentionedC₁₋₆ alkyl group by replacing one or more hydrogen atom(s) at arbitraryposition(s) by one or more identical or different halogen atoms selectedfrom the group consisting of fluorine atoms, chlorine atoms, bromineatoms and iodine atoms.

A “C₃₋₁₁ cycloalkane” is a monocyclic, fused, bridged or Spiro aliphatichydrocarbon ring having 3 to 11 ring-constituting carbon atoms and may,for example, be cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane, adamantane, bicyclo[3.1.0]octane,bicyclo[2.2.1]heptane, spiro[5.5]undecane or the like.

A “C₃₋₁₁ cycloalkyl group” is a monovalent group derived from theabove-mentioned “C₃₋₁₁ cycloalkane” by removing a hydrogen atom at anarbitrary position.

A “C₃₋₆ cycloalkane” is a ring having 3 to 6 ring-constituting carbonatoms among the above-mentioned “C₃₋₁₁ cycloalkane” and may, forexample, be cyclopropane, cyclobutane, cyclopentane, cyclohexane or thelike.

A “C₃₋₆ cycloalkyl group” is a group having 3 to 6 ring-constitutingcarbon atoms among the above-mentioned “C₃₋₁₁ cycloalkyl group”, andmay, for example, be a cyclopropyl group, a cyclobutyl group, acyclopentyl group, a cyclohexyl group or the like.

A “C₄₋₇ cycloalkane” is a ring having 4 to 7 ring-constituting carbonatoms among the above-mentioned “C₃₋₁₁ cycloalkane” and may, forexample, be cyclobutane, cyclopentane, cyclohexane, cycloheptane or thelike.

A “C₃₋₁₁ cycloalkene” is a non-aromatic ring derived from replacing oneor more bonds in the above-mentioned “C₃₋₁₁ cycloalkane” are replaced bydouble bond(s) and may, for example, be cyclopropene, cyclobutene,cyclopentene, cyclohexene, cyclohexa-1,3-diene, cyclohexa-1,4-diene,bicyclo[2.2.1]hepta-2,5-diene, spiro[2.5]oct-4-ene,1,2,5,6-tetrahydronaphthalene or the like.

A “C₂₋₆ alkenyl group” is a linear or branched alkenyl group having atleast one double bond and 2 to 6 carbon atoms and may, for example be anethenyl(vinyl) group, a 1-propenyl group, a 2-propenyl(allyl) group, anisopropenyl group, a 1-butenyl group, a 2-butenyl group, a3-butenyl(homoallyl) group, a 4-pentenyl group, a 5-hexenyl group or thelike.

A “C₂₋₃ alkenyl group” is an ethenyl(vinyl) group, a 1-propenyl group, a2-propenyl(allyl) group or an isopropenyl group.

A “C₂₋₆ haloalkenyl group” is a group derived from the above-mentioned“C₂₋₆ alkenyl group” by replacing one or more hydrogen atom(s) atarbitrary position(s) by one or more identical or different halogenatoms selected from the group consisting of fluorine atoms, chlorineatoms, bromine atoms and iodine atoms.

A “C₂₋₆ alkynyl group” is a linear or branched alkynyl group having atleast one triple bond and 2 to 6 carbon atoms and may, for example be anethynyl group, a 1-propynyl group, a 3-propynyl group, a 1-butynylgroup, a 2-butynyl group, a 3-butynyl group, a 4-pentynyl group, a5-hexynyl group, a 1,5-hexandiynyl group or the like.

A “C₁₋₆ alkoxy group” is a linear or branched alkoxy group having 1 to 6carbon atoms and may, for example, be a methoxy group, an ethoxy group,a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxygroup, a t-butoxy group, a n-pentyloxy group, a n-hexyloxy group or thelike.

A “C₁₋₃ alkoxy group” is a methoxy group, an ethoxy group, a n-propoxygroup or an i-propoxy group.

A “C₁₋₆ haloalkoxy group” is a group derived from the above-mentioned“C₁₋₆ alkoxy group” by replacing one or more hydrogen atom(s) atarbitrary position(s) by one or more identical or different halogenatoms selected from the group consisting of fluorine atoms, chlorineatoms, bromine atoms and iodine atoms.

A “C₁₋₃ haloalkoxy group” is a group derived from the above-mentioned“C₁₋₃ alkoxy group” by replacing one or more hydrogen atom(s) atarbitrary position(s) by one or more identical or different halogenatoms selected from the group consisting of fluorine atoms, chlorineatoms, bromine atoms and iodine atoms.

A “C₁₋₆ alkylene group” is a bivalent group derived from theabove-mentioned “C₁₋₆ alkyl group” by removing a hydrogen atom at anarbitrary position and may, for example, be a methylene group, anethylene group, a propane-1,3-diyl group, a propane-1,2-diyl group, a2,2-dimethyl-propane-1,3-diyl group, a hexane-1,6-diyl group, or a3-methylbutane-1,2-diyl group or the like.

A “C₁₋₃ alkylene group” is a methylene group, an ethylene group, apropane-1,3-diyl group or a propane-1,2-diyl group.

A “C₁₋₆ haloalkylene group” is a group derived from the above-mentioned“C₁₋₆ alkylene group” by replacing one or more hydrogen atom(s) atarbitrary position(s) by one or more identical or different halogenatoms selected from the group consisting of fluorine atoms, chlorineatoms, bromine atoms and iodine atoms.

A “C₁₋₃ haloalkylene group” is a group derived from the above-mentioned“C₁₋₃ alkylene group” by replacing one or more hydrogen atom(s) atarbitrary position(s) by one or more identical or different halogenatoms selected from the group consisting of fluorine atoms, chlorineatoms, bromine atoms and iodine atoms.

A “C₂₋₆ alkenylene group” is a bivalent group derived from theabove-mentioned “C₂₋₆ alkenyl group” by removing a hydrogen atom at anarbitrary position and may, for example, be an ethenylene group, anethene-1,1-diyl group, an ethane-1,2-diyl group, a propene-1,1-diylgroup, a propene-1,2-diyl group, a propene-1,3-diyl group, abut-1-ene-1,4-diyl group, a but-1-ene-1,3-diyl group, abut-2-ene-1,4-diyl group, a but-1,3-diene-1,4-diyl group, apent-2-ene-1,5-diyl group, a hex-3-ene-1,6-diyl group, ahexa-2,4-diene-1,6-diyl group or the like.

A “C₂₋₃ alkenylene group” is an ethene-1,1-diyl group, anethane-1,2-diyl group, a propene-1,1-diyl group, a propene-1,2-diylgroup, a propene-1,3-diyl group.

A “C₂₋₆ alkynylene group” is a linear or branched alkynylene grouphaving at least one triple bond and 2 to 6 carbon atoms and may, forexample, be an ethyn-1,2-diyl group, a propyn-1,2-diyl group, abut-1-yn-1,4-diyl group, a but-1-yn-1,3-diyl group, a but-2-yn-1,4-diylgroup, a pent-2-yn-1,5-diyl group, a pent-2-yn-1,4-diyl group, ahex-3-yn-1,6-diyl group or the like.

A “C₆₋₁₄ aromatic carbocycle” is a monocyclic, bicyclic or tricyclicaromatic carbocycle having 6 to 14 carbon atoms as the solering-constituting atoms and may, for example, be benzene, pentalene,naphthalene, azulene, anthracene, phenanthrene or the like.

A “C₆₋₁₄ aryl group” is a monovalent group derived from theabove-mentioned “C₆₋₁₄ aromatic carbocycle” by removing a hydrogen atomand may have the free valence at any position without particularrestriction.

A “5 to 10-membered aromatic heterocycle” is a monocyclic or fusedaromatic heterocyclyl group having 5 to 10 ring-constituting atomsincluding 1 to 5 hetero atoms (such as nitrogen atoms, oxygen atoms andsulfur atoms) and may, for example, be furan, thiophene, pyrrole,imidazole, triazole, tetrazole, thiazole, pyrazole, oxazole, isoxazole,isothiazole, thiadiazole, oxadiazole, pyridine, pyrazine, pyridazine,pyrimidine, triazine, purine, pteridine, quinoline, isoquinoline,naphthylidine, quinoxaline, cinnoline, quinazoline, phthalazine,imidazopyridine, imidazothiazole, imidazooxazole, benzothiazole,benzoxazole, benzimidazole, indole, isoindole, indazole,pyrrolopyridine, thienopyridine, furopyridine, benzothiadiazole,benzoxadiazole, pyridopyrimidine, benzofuran, benzothiophene,thienofuran or the like.

In the case of a “5 to 10-membered aromatic heterocycle” having a C═Ndouble bond, it may be in the form of an N-oxide.

A “5 to 10-membered aromatic heterocyclyl group” is a monovalent groupderived from the above-mentioned “5 to 10-membered aromatic heterocycle”by removing a hydrogen atom at an arbitrary position and may have thefree valence at any position without particular restrictions.

A “5 to 6-membered aromatic heterocycle” is a monocyclic group having 5to 6 ring-constituting atoms among the above-mentioned “5 to 10-memberedaromatic heterocycles” and may, for example, be pyrrole, pyrazole,imidazole, triazole, tetrazole, pyridine, pyridazine, pyrimidine,pyrazine, triazine, furan, thiophene, thiazole, isothiazole, oxazole,isoxazole, oxadiazole, thiadiazole or the like.

A “5 to 6-membered aromatic heterocyclyl group” is a monovalent groupderived from the above-mentioned “5 to 6-membered aromatic heterocycle”by removing a hydrogen atom at an arbitrary position and may have thefree valence at any position without particular restrictions.

A “3 to 14-membered non-aromatic heterocycle” is a non-aromaticheterocycle:

1) which has 3 to 14 ring-constituting atoms,2) the ring-constituting atoms of which contains 1 to 7 hetero atomsselected from nitrogen atoms, oxygen atoms or sulfur atoms,3) which may have one or more carbonyl groups, one or more double ortriple bonds in the ring system,4) which may contain one or more sulfur atoms in the form of sulfinyl orsulfonyl groups as ring-constituting atoms, and5) which may be a monocyclic ring, a fused ring (in the fused ring, anon-aromatic ring may be fused to non-aromatic ring(s) or toaromatic-ring(s)), a bridged ring or a spiro ring. It may, for example,be azetidine, pyrrolidine, piperidine, azepane, azocane,tetrahydrofuran, tetrahydropyran, morpholine, thiomorpholine,piperazine, thiazolidine, 1,4-dioxane, imidazoline, thiazoline,benzopyran, isochroman, chroman, indoline, isoindoline, azaindane,tetrahydroazanaphthalene, azachroman, tetrahydrobenzofuran,tetrahydrobenzothiophene, 2,3,4,5-tetrahydro-benzo[b]thiophene,3,4-dihydro-2H-benzo[b][1,4]dioxepane,6,7-dihydro-5H-cyclopenta[b]pyrazine,5,6-dihydro-4H-cyclopenta[b]thiophene,4,5,6,7-tetrahydrobenz[b]thiophene, 2,3-dihydroisoindol-1-one,3,4-dihydro-2H-isoquinolin-1-one, 3,4-dihydro-2H-benzo[b]oxepin-5-one,2,3,4,4a,9,9a-hexahydro-1H-carbazole,1′H-spiro[cyclopropane-1,2-quinoxalin]-3′(4′H)-one, 10H-phenoxazine,[1,3]dioxolo[4,5-f]quinoline or the like.

A “3 to 14-membered non-aromatic heterocyclyl group” is a monovalentgroup derived from the above-mentioned “3 to 14-membered non-aromaticheterocycle” by removing a hydrogen atom at an arbitrary position. Itmay have the free valence at any position without particularrestrictions, but in the case of an fused ring system consisting of anon-aromatic ring fused to an aromatic ring, it has the free valence inthe non-aromatic ring.

A “3 to 11-membered non-aromatic heterocycle” is non-aromaticheterocycle:

1) which has 3 to 11 ring-constituting atoms2) the ring-constituting atoms of which contains 1 to 5 hetero atomsselected from nitrogen atoms, oxygen atoms or sulfur atoms,3) which may have one or more carbonyl groups, one or more double ortriple bonds in the ring system,4) which may contain one or more sulfur atoms in the form of sulfinyl orsulfonyl groups as ring-constituting atoms, and5) which may be a monocyclic ring, a fused ring (in the fused ring, anon-aromatic ring may be fused to non-aromatic ring(s) or toaromatic-ring(s)), a bridged ring or a spiro ring. It may, for example,be azetidine, pyrrolidine, piperidine, azepane, azocane,tetrahydrofuran, tetrahydropyran, morpholine, thiomorpholine,piperazine, thiazolidine, 1,4-dioxane, imidazoline, thiazoline,benzopyran, isochroman, chroman, indoline, isoindoline, azaindane,tetrahydroazanaphthalene, azachroman, tetrahydrobenzofuran,tetrahydrobenzothiophene, 2,3,4,5-tetrahydro-benzo[b]thiophene,3,4-dihydro-2H-benzo[b][1,4]oxepine,6,7-dihydro-5H-cyclopenta[b]pyrazine,5,6-dihydro-4H-cyclopenta[b]thiophene,4,5,6,7-tetrahydrobenzo[b]thiophene, 2,3-dihydroisoindol-1-one,3,4-dihydro2H-isoquinolin-1-one, 3,4-dihydro2H-benzo[b]oxepin-5-one orthe like.

A 3 to 11-membered non-aromatic heterocyclyl group” is a monovalentgroup derived from the above-mentioned “3 to 11-membered non-aromaticheterocycle” by removing a hydrogen atom at an arbitrary position. Itmay have the free valence at any position without particularrestrictions, but in the case of an fused ring system consisting of anon-aromatic ring fused to an aromatic ring, it has the free valence inthe non-aromatic ring.

A “4 to 7-membered non-aromatic heterocycle” is a monocyclicnon-aromatic heterocycle:

1) which has 4 to 7 ring-constituting atoms2) the ring-constituting atoms of which contains 1 to 3 hetero atomsselected from nitrogen atoms, oxygen atoms and sulfur atoms,3) which may have one or more carbonyl groups, one or more double ortriple bonds in the ring system, and4) which may contain one or more sulfur atoms in the form of sulfinyl orsulfonyl groups as ring-constituting atoms. It may, for example, beazetidine, pyrrolidine, pyrrolidinone, oxazolidine, isoxazolidine,thiazolidine, isothiazolidine, piperazine, piperazinone, piperidine,piperidinone, morpholine, thiomorpholine, azepine, diazepine, oxetane,tetrahydrofuran, 1,3-dioxorane, tetrahydropyran, 1,4-dioxane, oxepane,homomorpholine or the like.

A “4 to 7-membered non-aromatic heterocyclyl group” is a monovalentgroup derived from the above-mentioned “4 to 7-membered non-aromaticheterocycle” by removing a hydrogen atom at an arbitrary position andmay have the free valence at any position without particularrestrictions.

A “C₁₋₆ alkylthio group” is a group consisting of the above-mentioned“C₁₋₆ alkyl group” attached to a sulfur atom and may, for example, be amethylthio group, an ethylthio group, a n-propylthio group, anisopropylthio group, a n-butylthio group, an isobutylthio group, at-butylthio group, a n-pentylthio group, a n-hexylthio group or thelike.

A “C₁₋₃ alkylthio group” is a group consisting of the above-mentioned“C₁₋₃ alkyl group” attached to a sulfur atom and may, for example, be amethylthio group, an ethylthio group, a n-propylthio group or anisopropylthio group.

A “C₁₋₆ haloalkylthio group” is a group derived from the above-mentioned“C₁₋₆ alkylthio group” by replacing one or more hydrogen atom(s) atarbitrary position(s) by one or more identical or different halogenatoms selected from the group consisting of fluorine atoms, chlorineatoms, bromine atoms and iodine atoms.

A “C₁₋₃ haloalkylthio group” is a group derived from the above-mentioned“C₁₋₃ alkylthio group” by replacing one or more hydrogen atom(s) atarbitrary position(s) by one or more identical or different halogenatoms selected from the group consisting of fluorine atoms, chlorineatoms, bromine atoms and iodine atoms.

A “C₁₋₆ alkylsulfonyl group” is a group consisting of theabove-mentioned “C₁₋₆ alkyl group” attached to a sulfonyl group and may,for example, be a methylsulfonyl group, an ethylsulfonyl group, an-propylsulfonyl group, an isopropylsulfonyl group, a n-butylsulfonylgroup, an isobutylsulfonyl group, a t-butylsulfonyl group, an-pentylsulfonyl group, a n-hexylsulfonyl group or the like.

A “C₁₋₃ alkylsulfonyl group” is a group consisting of theabove-mentioned “C₁₋₃ alkyl group” attached to a sulfonyl group and may,for example, be a methylsulfonyl group, an ethylsulfonyl group, an-propylsulfonyl group or an isopropylsulfonyl group.

A “C₁₋₆ haloalkylsulfonyl group” is a group derived from theabove-mentioned “C₁₋₆ alkylsulfonyl group” by replacing one or morehydrogen atom(s) at arbitrary position(s) by one or more identical ordifferent halogen atoms selected from the group consisting of fluorineatoms, chlorine atoms, bromine atoms and iodine atoms.

A “C₁₋₃ haloalkylsulfonyl group” is a group derived from theabove-mentioned “C₁₋₃ alkylsulfonyl group” by replacing one or morehydrogen atom(s) at arbitrary position(s) by one or more identical ordifferent halogen atoms selected from the group consisting of fluorineatoms, chlorine atoms, bromine atoms and iodine atoms.

A “C₁₋₆ alkoxycarbonyl group” is a group consisting of theabove-mentioned “C₁₋₆ alkoxy group” attached to a carbonyl group andmay, for example, be a methoxycarbonyl group, an ethoxycarbonyl group, an-propoxycarbonyl group, an isopropoxycarbonyl group, a n-butoxycarbonylgroup, an isobutoxycarbonyl group, a t-butoxycarbonyl group, an-pentyloxycarbonyl group, a n-hexyloxycarbonyl group or the like.

A “C₁₋₃ alkoxycarbonyl group” is a methoxycarbonyl group, anethoxycarbonyl group, a n-propoxycarbonyl group or an isopropoxycarbonylgroup.

A “mono-C₁₋₆ alkylamino group” is a group consisting of theabove-mentioned “C₁₋₆ alkyl group” attached to an amino group and may,for example, be a methylamino group, an ethylamino group, an-propylamino group, an isopropylamino group, a n-butylamino group, anisobutylamino group, a t-butylamino group, a n-pentylamino group, an-hexylamino group or the like.

A “mono-C₁₋₃ alkylamino group” is a methylamino group, an ethylaminogroup, a n-propylamino group or an isopropylamino group.

A “di-C₁₋₆ alkylamino group” is a group consisting of an amino groupattached to two identical or different “C₁₋₆ alkyl groups” such as thosementioned above and may, for example, be a dimethylamino group, adiethylamino group, a di-n-propylamino group, a diisopropylamino group,a di-n-butylamino group, a diisobutylamino group, a di-t-butylaminogroup, a di-n-pentylamino group, a di-n-hexylamino group, anN-ethyl-N-methylamino group, an N-methyl-N-n-propylamino group, anN-isopropyl-N-methylamino group, an N-n-butyl-N-methylamino group, anN-isobutyl-N-methylamino group, an N-t-butyl-N-methylamino group, anN-methyl-N-n-pentylamino group, N-n-hexyl-N-methylamino group, anN-ethyl-N-n-propylamino group, an N-ethyl-N-isopropylamino group, anN-n-butyl-N-ethylamino group, an N-ethyl-N-isobutylamino group, anN-t-butyl-N-ethylamino group, an N-ethyl-N-n-pentylamino group, anN-ethyl-N-n-hexylamino group or the like.

A “di-C₁₋₃ alkylamino group” is a dimethylamino group, a diethylaminogroup, a di-n-propylamino group, a diisopropylamino group, anN-ethyl-N-methylamino group, an N-methyl-N-n-propylamino group, anN-isopropyl-N-methylamino group, an N-ethyl-N-n-propylamino group or anN-ethyl-N-isopropylamino group.

A “C₁₋₆ alkylcarbonyl group” is a group consisting of theabove-mentioned “C₁₋₆ alkyl group” attached to a carbonyl group and may,for example, be an acetyl group, a propionyl group, a butyryl group, anisobutyryl group, a pentanoyl group, a 3-methylbutanoyl group, apivaloyl group, a hexanoyl group or a heptanoyl group.

A “C₁₋₃ alkylcarbonyl group” is an acetyl group, a propionyl group, abutyryl group or an isobutyryl group.

A “C₁₋₆ haloalkylcarbonyl group” is a group derived from theabove-mentioned “C₁₋₆ alkylcarbonyl group” by replacing one or morehydrogen atom(s) at arbitrary position(s) by one or more identical ordifferent halogen atoms selected from the group consisting of fluorineatoms, chlorine atoms, bromine atoms and iodine atoms.

A “C₁₋₃ haloalkylcarbonyl group” is a group derived from theabove-mentioned “C₁₋₃ alkylcarbonyl group” by replacing one or morehydrogen atom(s) at arbitrary position(s) by one or more identical ordifferent halogen atoms selected from the group consisting of fluorineatoms, chlorine atoms, bromine atoms and iodine atoms.

A “mono-C₁₋₆ alkylaminocarbonyl group” is a group consisting of theabove-mentioned “mono-C₁₋₆ alkylamino group” attached to a carbonylgroup and may, for example, be a methylaminocarbonyl group, anethylaminocarbonyl group, a n-propylaminocarbonyl group, anisopropylaminocarbonyl group, a n-butylaminocarbonyl group, anisobutylaminocarbonyl group, a t-butylaminocarbonyl group, an-pentylaminocarbonyl group, a n-hexylaminocarbonyl group or the like.

A “mono-C₁₋₃ alkylaminocarbonyl group” is a methylaminocarbonyl group,an ethylaminocarbonyl group, a n-propylaminocarbonyl group or anisopropylaminocarbonyl group.

A “di-C₁₋₆ alkylaminocarbonyl group” is a group consisting of theabove-mentioned “di-C₁₋₆ alkylamino group” attached to a carbonyl groupand may, for example, be a dimethylaminocarbonyl group, adiethylaminocarbonyl group, a di-n-propylaminocarbonyl group, adiisopropylaminocarbonyl group, a di-n-butylaminocarbonyl group, adiisobutylaminocarbonyl group, a di-t-butylaminocarbonyl group, adi-n-pentylaminocarbonyl group, a di-n-hexylaminocarbonyl group, anN-ethyl-N-methylaminocarbonyl group, an N-methyl-N-n-propylaminocarbonylgroup, an N-isopropyl-N-methylaminocarbonyl group, anN-n-butyl-N-methylaminocarbonyl group, anN-isobutyl-N-methylaminocarbonyl group, anN-t-butyl-N-methylaminocarbonyl group, anN-methyl-N-n-pentylaminocarbonyl group, anN-n-hexyl-N-methylaminocarbonyl group, anN-ethyl-N-n-propylaminocarbonyl group, anN-ethyl-N-isopropylaminocarbonyl group, anN-n-butyl-N-ethylaminocarbonyl group, an N-ethyl-N-isobutylaminocarbonylgroup, an N-t-butyl-N-ethylaminocarbonyl group, anN-ethyl-N-n-pentylaminocarbonyl group, an N-ethyl-N-n-hexylaminocarbonylgroup or the like.

A “di-C₁₋₃ alkylaminocarbonyl group” is a dimethylaminocarbonyl group, adiethylaminocarbonyl group, a di-n-propylaminocarbonyl group, adiisopropylaminocarbonyl group, an N-ethyl-N-methylaminocarbonyl group,an N-methyl-N-n-propylaminocarbonyl group, anN-isopropyl-N-methylaminocarbonyl group, N-ethyl-N-n-propylaminocarbonylgroup, or an N-ethyl-N-isopropylaminocarbonyl group.

A “C₁₋₆ alkylcarbonylamino group” is a group consisting of theabove-mentioned “C₁₋₆ alkylcarbonyl group” attached to an amino groupand may, for example, be a methylcarbonylamino group, anethylcarbonylamino group, a n-propylcarbonylamino group, anisopropylcarbonylamino group, a n-butylcarbonylamino group, anisobutylcarbonylamino group, a t-butylcarbonylamino group, an-pentylcarbonylamino group, a n-hexylcarbonylamino group or the like.

A “C₁₋₃ alkylcarbonylamino group” is a methylcarbonylamino group, anethylcarbonylamino group, a n-propylcarbonylamino group or anisopropylcarbonylamino group.

A “mono-C₁₋₆ alkylaminosulfonyl group” is a group consisting of theabove-mentioned “mono-C₁₋₆ alkylamino group” attached to a sulfonylgroup and may, for example, be a methylaminosulfonyl group, anethylaminosulfonyl group, a n-propylaminosulfonyl group, anisopropylaminosulfonyl group, a n-butylaminosulfonyl group, anisobutylaminosulfonyl group, a t-butylaminosulfonyl group, an-pentylaminosulfonyl group, a n-hexylaminosulfonyl group or the like.

A “mono-C₁₋₃ alkylaminosulfonyl group” is a methylaminosulfonyl group,an ethylaminosulfonyl group, a n-propylaminosulfonyl group or anisopropylaminosulfonyl group.

A “di-C₁₋₆ alkylaminosulfonyl group” is a group consisting of theabove-mentioned “di-C₁₋₆ alkylamino group” attached to a sulfonyl groupand may, for example, be a dimethylaminosulfonyl group, adiethylaminosulfonyl group, a di-n-propylaminosulfonyl group, adiisopropylaminosulfonyl group, a di-n-butylaminosulfonyl group, adiisobutylaminosulfonyl group, a di-t-butylaminosulfonyl group, adi-n-pentylaminosulfonyl group, a di-n-hexylaminosulfonyl group, anN-ethyl-N-methylaminosulfonyl group, an N-methyl-N-n-propylaminosulfonylgroup, an N-isopropyl-N-methylaminosulfonyl group, anN-n-butyl-N-methylaminosulfonyl group, anN-isobutyl-N-methylaminosulfonyl group, anN-t-butyl-N-methylaminosulfonyl group, anN-methyl-N-n-pentylaminosulfonyl group, N-n-hexyl-N-methylaminosulfonylgroup, an N-ethyl-N-n-propylaminosulfonyl group, anN-ethyl-N-isopropylaminosulfonyl group, anN-n-butyl-N-ethylaminosulfonyl group, an N-ethyl-N-isobutylaminosulfonylgroup, an N-t-butyl-N-ethylaminosulfonyl group, anN-ethyl-N-n-pentylaminosulfonyl group, an N-ethyl-N-n-hexylaminosulfonylgroup or the like.

A “di-C₁₋₃ alkylaminosulfonyl group” is a dimethylaminosulfonyl group, adiethylaminosulfonyl group, a di-n-propylaminosulfonyl group, adiisopropylaminosulfonyl group, an N-ethyl-N-methylaminosulfonyl group,an N-methyl-N-n-propylaminosulfonyl group, anN-isopropyl-N-methylaminosulfonyl group, anN-ethyl-N-n-propylaminosulfonyl group, or anN-ethyl-N-isopropylaminosulfonyl group or anN-isopropyl-N-n-propylaminosulfonyl group.

A “C₁₋₆ alkylsulfonylamino group” is a group consisting of theabove-mentioned “C₁₋₆ alkylsulfonyl group” attached to an amino groupand may, for example, be a methylsulfonylamino group, anethylsulfonylamino group, a n-propylsulfonylamino group, anisopropylsulfonylamino group, a n-butylsulfonylamino group, anisobutylsulfonylamino group, a t-butylsulfonylamino group, an-pentylsulfonylamino group, a n-hexylsulfonylamino group or the like.

A “C₁₋₆ alkoxycarbonylamino group” is a group consisting of theabove-mentioned “C₁₋₆ alkoxycarbonyl group” attached to an amino groupand may, for example, be a methoxycarbonylamino group, anethoxycarbonylamino group, a n-propoxycarbonylamino group, anisopropoxycarbonylamino group, a n-butoxycarbonylamino group, anisobutoxycarbonylamino group, a t-butoxycarbonylamino group, an-pentyloxycarbonylamino group, a n-hexyloxycarbonylamino group or thelike.

A “C₃₋₆ cycloalkoxy group” is a group consisting of the above-mentioned“C₃₋₆ cycloalkyl group” attached to an oxygen atom and may, for example,be a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, acyclohexyloxy group or the like.

A “C₃₋₆ cycloalkylamino group” is a group consisting of theabove-mentioned “C₃₋₆ cycloalkyl group” attached to an amino group andmay, for example, be a cyclopropylamino group, a cyclobutylamino group,a cyclopentylamino group, a cyclohexylamino group or the like.

A “di-C₃₋₆ cycloalkylamino group” is a group consisting of an aminogroup attached to two identical or different “C₃₋₆ cycloalkyl groups”such as those mentioned above and may, for example, be adicyclopropylamino group, a dicyclobutylamino group, a dicylopentylaminogroup, a dicyclohexylamino group or the like.

A “C₃₋₆ cycloalkylthio group” is a group consisting of the “C₃₋₆cycloalkyl group” attached to —S— and may, for example, be acyclopropylthio group, a cyclobutylthio group, a cyclopentylthio group,a cyclohexylthio group or the like.

A “C₃₋₆ cycloalkylcarbonyl group” is a group consisting of theabove-mentioned “C₃₋₆ cycloalkyl group” attached to a carbonyl group andmay, for example, be a cyclopropylcarbonyl group, a cyclobutylcarbonylgroup, a cyclopentylcarbonyl group, a cyclohexylcarbonyl group or thelike.

A “C₃₋₆ cycloalkylsulfonyl group” is a group consisting of theabove-mentioned “C₃₋₆ cycloalkyl group” attached to a sulfonyl group andmay, for example, be a cyclopropylsulfonyl group, a cyclobutylsulfonylgroup, a cyclopentylsulfonyl group, a cyclohexylsulfonyl group or thelike.

A “8 to 14-membered aromatic ring-condensed alicyclic hydrocarbon” is afused ring system:

1) which has 8 to 14 ring-constituting atoms,2) all the ring-constituting atoms of which are carbon atoms,3) which may have one or more carbonyl groups, one or more double ortriple bonds in the ring system, and4) which consists of non-aromatic ring(s) fused to aromatic-ring(s). Itmay, for example, be 1H-indene, 2,3-dihydroindene, 1H-inden-1-on,1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene,3,4-dihydronaphthalen-1(2H)-on,1,2,3,4-tetrahydro-1,4-methanonaphthalene,1,2,3,4-tetrahydrophenanthrene, 2,3-dihydro-1H-phenalene, 9H-fluorene orthe like.

A “8 to 14-membered aromatic ring-condensed alicyclic hydrocarbon group”is a monovalent group derived from the above-mentioned “8 to 14-memberedaromatic ring-condensed alicyclic hydrocarbon” by removing a hydrogenatom at an arbitrary position. It may have the free valence at anyposition in the alicyclic carbocycle without particular restrictions.

It may, for example, be a 1H-inden-1-yl group, a 1H-inden-2-yl group, a1H-inden-3-yl group, a 1,2,3,4-tetrahydronaphthalen-1-yl group, a1,2,3,4-tetrahydronaphthalen-2-yl group, a1,2,3,4-tetrahydronaphthalen-3-yl group, a1,2,3,4-tetrahydronaphthalen-4-yl group, a4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl group, a 9H-fluoren-9-yl groupor the like.

A “8 to 14-membered partially saturated aromatic cyclic group” is agroup derived from 1) a bicyclic or tricyclic ring having 8 to 14ring-constituting atoms and consisting of a non-aromatic ring fused toaromatic rings among the above-mentioned “3 to 14-membered non-aromaticheterocycle” or 2) the above-mentioned “8 to 14-membered aromaticring-condensed alicyclic hydrocarbon” by removing a hydrogen atom at anarbitrary position. It may have the free valence at any position in thearomatic ring without particular restrictions.

It may, for example, be a 1H-inden-4-yl group, a 1H-inden-5-yl group, a1H-inden-6-yl group, a 1H-inden-7-yl group, a5,6,7,8-tetrahydronaphthalen-1-yl group, a5,6,7,8-tetrahydronaphthalen-2-yl group, a5,6,7,8-tetrahydronaphthalen-3-yl group, a5,6,7,8-tetrahydronaphthalen-4-yl group, a 9H-fluorene2-yl group, anindolin-4-yl group, an indolin-5-yl group, an indolin-6-yl group, anindolin-7-yl group, a chroman-5-yl group, a chroman-6-yl group, achroman-7-yl group, a chroman-8-yl group, a4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl group, a2,3,4,4a,9,9a-hexahydro-1H-carbazol-5-yl group or the like.

A “8 to 11-membered aromatic ring-condensed alicyclic hydrocarbon” is afused ring system:

1) which has 8 to 11 ring-constituting atoms,2) all the ring-constituting atoms of which are carbon atoms,3) which may have one or more carbonyl groups, one or more double ortriple bonds in the ring system, and4) which consists of an alicyclic hydrocarbon fused to a benzene ring,and it may, for example, be 1H-indene, 2,3-dihydroindene, 1H-inden-1-on,1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene,3,4-dihydronaphthalen-1(2H)-one or the like.

A “8 to 11-membered aromatic ring-condensed alicyclic hydrocarbon group”is a group derived from the above-mentioned “8 to 11-membered aromaticring-condensed alicyclic hydrocarbon” by removing a hydrogen atom at anarbitrary position. and may have the free valence at any position in thealicyclic carbocycle without particular restrictions.

It may, for example, be a 1H-inden-4-yl group, a 1H-inden-5-yl group, a1H-inden-6-yl group, a 1H-inden-7-yl group, a5,6,7,8-tetrahydronaphthalen-1-yl group, a5,6,7,8-tetrahydronaphthalen-2-yl group, a5,6,7,8-tetrahydronaphthalen-3-yl group, a5,6,7,8-tetrahydronaphthalen-4-yl group or the like.

A “8 to 11-membered partially saturated aromatic cyclic group” is agroup derived from 1) a partially saturated aromatic ring having 8 to 11ring-constituting atoms and consisting of an aromatic ring fused to anon-aromatic ring or 2) the above-mentioned “8 to 11-membered aromaticring-condensed alicyclic hydrocarbon group” by removing a hydrogen atomat an arbitrary position. and may have the free valence at any positionin the aromatic ring without particular restrictions.

It may, for example, be a 1H-inden-4-yl group, a 1H-inden-5-yl group, a1H-inden-6-yl group, a 1H-inden-7-yl group, a5,6,7,8-tetrahydronaphthalen-1-yl group, a5,6,7,8-tetrahydronaphthalen-2-yl group, a5,6,7,8-tetrahydronaphthalen-3-yl group, a5,6,7,8-tetrahydronaphthalen-4-yl group, an indolin-4-yl group, anindolin-5-yl group, an indolin-6-yl group, an indolin-7-yl group, achroman-5-yl group, a chroman-6-yl group, a chroman-7-yl group, achroman-8-yl group, 4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl group or thelike.

Now, the tricyclic pyrimidine compounds of the present inventionrepresented by the formula (I^(a)) will be described.

First, how the ring A^(a) is fused in the tricyclic pyrimidine compoundsof the present invention will be described.

As is indicated in the formula (I^(a)), the ring A^(a) is fused to thepyrimidine ring so as to have a carbon atom and a nitrogen atom incommon and attached to L^(1a) via a carbon atom in the ring A^(a) in theformula (I^(a)).

Therefore, when the ring A^(a) is represented by the formula (II^(a)-1),

the molecule as a whole is represented by the formula (I^(a))-2:

and when the ring A^(a) is represented by the formula (II^(a)-2),

the molecule as a whole is represented by the formula (I^(a))-3.

In the present invention, the formulae representing L^(3a) indicate thatthe left ends of the formulae are bonded to L^(2a), and the right endsof the formulae are bonded to R^(2a).

In the present invention, L^(1a), L^(2a) and R^(3a) may be bounded tothe ring B^(a) in the formula (I^(a)) at any positions of the ring B^(a)without any particular restrictions.

Next, preferred structures of the respective substituents will bementioned.

A preferred embodiment of the substituent R^(1a) is a hydrogen atom or ahalogen atom.

A more preferred embodiment of the substituent R^(1a) is a hydrogenatom.

A preferred embodiment of the substituent Y^(a) is CR^(10a) (whereinR^(10a) is a hydrogen atom, a halogen atom, a cyano group, a C₁₋₆ alkylgroup, a C₁₋₆ haloalkyl group or a C₃₋₆ cycloalkyl group).

A more preferred embodiment of the substituent Y^(a) is CR^(10a)(wherein R^(10a) is a hydrogen atom).

A preferred embodiment of the substituent X^(a) is CR^(9a) (whereinR^(9a) is a hydrogen atom, a halogen atom, a cyano group, a C₁₋₆ alkylgroup, a C₁₋₆ haloalkyl group or a C₃₋₆ cycloalkyl group) or a nitrogenatom.

A more preferred embodiment of the substituent X^(a) is CR^(9a) (whereinR^(9a) is a hydrogen atom).

Another more preferred embodiment of the substituent X^(a) is CR^(9a)(wherein R^(9a) is a halogen atom).

A preferred embodiment of the ring A^(a) is represented by any of thefollowing formulae (VII^(a)-1) to (VII^(a)-4):

(wherein E^(2a) is an oxygen atom or a sulfur atom, each of R^(4a),R^(7a) and R^(8a) is independently a hydrogen atom, an amino group, acarbamoyl group, a halogen atom, a cyano group, a C₁₋₆ alkyl group, aC₁₋₆ alkoxy group, a C₁₋₆ alkylthio group, a C₁₋₆ alkylsulfonyl group(the C₁₋₆ alkyl group, the C₁₋₆ alkoxy group, the C₁₋₆ alkylthio groupand the C₁₋₆ alkylsulfonyl group are unsubstituted or substituted withone or more identical or different substituents independently selectedfrom the substituent set V^(3a)), a C₃₋₆ cycloalkyl group, a 4 to7-membered non-aromatic heterocyclyl group, a phenyl group or a 5 to6-membered aromatic heterocyclyl group (the C₃₋₆ cycloalkyl group, the 4to 7-membered non-aromatic heterocyclyl group, the phenyl group and the5 to 6-membered aromatic heterocyclyl group are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the substituent set V^(1a)), and R^(ha) is ahydrogen atom, a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is unsubstitutedor substituted with one or more identical or different substituentsindependently selected from the substituent set V^(3a)), a C₃₋₆cycloalkyl group, a 4 to 7-membered non-aromatic heterocyclyl group, aphenyl group or a 5 to 6-membered aromatic heterocyclyl group (the C₃₋₆cycloalkyl group, the 4 to 7-membered non-aromatic heterocyclyl group,the phenyl group and the 5 to 6-membered aromatic heterocyclyl group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(1a))).

A more preferred embodiment of the ring A^(a) is represented by any ofthe following

formulae (IV^(a)-1) to (IV^(a)-3):

(wherein E^(2a) is an oxygen atom or a sulfur atom, R^(4a) is a hydrogenatom, a halogen atom, a C₁₋₃ alkyl group, a C₁₋₃ alkoxy group, a C₁₋₃alkylthio group or a C₁₋₃ alkylsulfonyl group, and R^(6a) is a hydrogenatom or a C₁₋₃ alkyl group).

A further preferred embodiment of the ring A^(a) is represented by anyof the following formulae (VIII^(a)-1) to (VIII^(a)-5).

A particularly preferred embodiment of the ring A^(a) is represented bythe formula (XXX^(a)).

A preferred embodiment of the substituent L^(1a) is a single bond or aC₁₋₃ alkylene group.

A more preferred embodiment of the substituent L^(1a) is a single bondor a methylene group.

A further preferred embodiment of the substituent L^(1a) is a singlebond.

A preferred embodiment of the ring B^(a) is a C₃₋₁₁ cycloalkane, a 3 to11-membered non-aromatic heterocycle, a C₆₋₁₄ aromatic carbocycle or a 5to 10-membered aromatic heterocycle.

Another preferred embodiment of the ring B^(a) is a C₃₋₁₁ cycloalkane (aring-constituting methylene group of the C₃₋₁₁ cycloalkane and the C₃₋₁₁cycloalkene is replaced by a carbonyl group).

A more preferred embodiment of the ring Er is a C₄₋₇ cycloalkane, a 4 to7-membered non-aromatic heterocycle, benzene or a 5 to 6-memberedaromatic heterocycle.

Another more preferred embodiment of the ring Er is a C₄₋₇ cycloalkane(a ring-constituting methylene group of the C₄₋₇ cycloalkane is replacedby a carbonyl group).

Another more preferred embodiment of the ring B^(a) is spiro[2,5]octaneor adamantane.

A further preferred embodiment of the ring B^(a) is azetidine,pyrrolidine, piperidine, azepane, cyclobutane, cyclopentane,cyclohexane, bicyclo[2.2.1]heptane, cycloheptane or benzene.

Another further preferred embodiment of the ring B^(a) is cyclohexanone.

A particularly preferred embodiment of the ring B^(a) is cyclohexane orpiperidine.

A preferred embodiment of the substituent L^(2a) is a single bond, aC₁₋₃ alkylene group or a C₁₋₃ haloalkylene group (the C₁₋₃ alkylenegroup and the C₁₋₃ haloalkylene group are substituted with a cyanogroup).

Another preferred embodiment of the substituent L^(2a) is a C₁₋₃alkylene group or a C₁₋₃ haloalkylene group (the C₁₋₃ alkylene group andthe C₁₋₃ haloalkylene group are unsubstituted or substituted with ahydroxy group).

Another preferred embodiment of the substituent L^(2a) is a C₂₋₃alkenylene group (the C₂₋₃ alkenylene group is unsubstituted orsubstituted with a hydroxy group or a cyano group).

Another preferred embodiment of the substituent L^(2a) is a C₁₋₃alkylene group or a C₂₋₃ alkenylene group (the C₁₋₃ alkylene group andthe C₂₋₃ alkenylene group are substituted with two cyano groups).

Another preferred embodiment of the substituent L^(2a) is a C₁₋₆alkylene group or a C₂₋₆ alkenylene group (the C₁₋₆ alkylene group andthe C₂₋₆ alkenylene group are unsubstituted or substituted with one ortwo cyano groups) or a C₁₋₆ haloalkylene.

Another preferred embodiment of the substituent L^(2a) is ═C(R^(15a))—(wherein R^(15a) is a hydrogen atom or a cyano group, and the bondconnecting the ring Er and L^(2a) is a double bond) or ═C(R^(15a))—CH₂—(wherein R^(15a) is a cyano group, and the bond connecting the ringB^(a) and L^(2a) is a double bond).

A more preferred embodiment of the substituent L^(2a) is a single bondor a methylene group (the methylene group is unsubstituted orsubstituted with one or more identical or different halogen atomsindependently selected from the group consisting of fluorine atoms,chlorine atoms, bromine atoms and iodine atoms or with a hydroxy group).

Another more preferred embodiment of the substituent L^(3a) is anethylene group (the ethylene group is unsubstituted or substituted withone or more identical or different halogen atoms independently selectedfrom the group consisting of fluorine atoms, chlorine atoms, bromineatoms and iodine atoms or with a hydroxy group) or a propylene group.

Another more preferred embodiment of the substituent L^(2a) is a C₁₋₃alkylene group (the C₁₋₃ alkylene group is substituted with a cyanogroup).

Another more preferred embodiment of the substituent L^(2a) is a C₁₋₃alkylene group (the C₁₋₃ alkylene group is substituted with two cyanogroups).

Another more preferred embodiment of the substituent L^(2a) is a C₂₋₃alkenylene group (the C₂₋₃ alkenylene group is substituted with a cyanogroup).

Another more preferred embodiment of the substituent L^(2a) is a C₂₋₃alkenylene group (the C₂₋₃ alkenylene group is substituted with twocyano groups).

A further preferred embodiment of the substituent L^(2a) is a singlebond or a methylene group.

Another further preferred embodiment of the substituent L^(2a) is a C₁₋₃alkylene group (the C₁₋₃ alkylene group is substituted with one or twocyano groups).

A preferred embodiment of the substituent L^(3a) and the substituentR^(2a) is such that L^(3a) is a single bond, and R^(2a) is a hydrogenatom, a halogen atom, a C₃₋₆ cycloalkyl group, a 3 to 11-memberednon-aromatic heterocyclyl group, a phenyl group or a 5 to 10-memberedaromatic heterocyclyl group (the C₃₋₆ cycloalkyl group, the 3 to11-membered non-aromatic heterocyclyl group, the phenyl group and the 5to 10-membered aromatic heterocyclyl group are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the substituent set V^(1a)).

Another preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is a single bond, and R^(2a) is ahydrogen atom, a halogen atom, an azido group, a C₃₋₆ cycloalkyl group,a 3 to 11-membered non-aromatic heterocyclyl group, a phenyl group or a5 to 10-membered aromatic heterocyclyl group (the C₃₋₆ cycloalkyl group,the 3 to 11-membered non-aromatic heterocyclyl group, the phenyl groupand the 5 to 10-membered aromatic heterocyclyl group are unsubstitutedor substituted with one or more identical or different substituentsindependently selected from the group consisting of the substituent setV^(4a), the substituent set V^(9a) and C₁₋₆ alkyl groups (the C₁₋₆ alkylgroups are substituted with a C₁₋₆ alkoxycarbonylamino group (the C₁₋₆alkoxycarbonylamino group is unsubstituted or substituted with one ormore identical or different halogen atoms independently selected fromthe group consisting of fluorine atoms, chlorine atoms, bromine atomsand iodine atoms))).

Another preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is a single bond, and R^(2a) is a8 to 11-membered partially saturated aromatic cyclic group (the 8 to11-membered partially saturated aromatic cyclic group is unsubstitutedor substituted with one or more identical or different substituentsindependently selected from the substituent set V^(1a)).

Another preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by any of thefollowing formulae (V^(a)-1) to (V^(a)-11):

(wherein E^(1a) is an oxygen atom or a sulfur atom, and each of R^(12a)and R^(13a) is independently a hydrogen atom, a C₁₋₆ alkyl group or aC₁₋₆ haloalkyl group), and R^(2a) is a hydrogen atom, a C₁₋₆ alkyl group(the C₁₋₆ alkyl group is unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(5a)), a C₂₋₆ alkenyl group, a C₃₋₆ cycloalkyl group,a 3 to 11-membered non-aromatic heterocyclyl group, a phenyl group or a5 to 10-membered aromatic heterocyclyl group (the C₂₋₆ alkenyl group,the C₃₋₆ cycloalkyl group, the 3 to 11-membered non-aromaticheterocyclyl group, the phenyl group and the 5 to 10-membered aromaticheterocyclyl group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(4a)).

Another preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by any of thefollowing formulae (XIV^(a)-1) to (XIV^(a)-15) and (XIII^(a)):

(wherein E^(1a) is an oxygen atom, a sulfur atom or NR^(11a) (whereinR^(11a) is a hydroxy group), and each of R^(12a) and R^(13a) isindependently a hydrogen atom, a C₁₋₆ alkyl group or a C₁₋₆ haloalkylgroup), and R^(2a) is a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆alkenyl group, a C₂₋₆ alkynyl group (the C₁₋₆ alkyl group, the C₂₋₆alkenyl group and the C₂₋₆ alkynyl group are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the substituent set V^(6a) and thesubstituent set V^(9a)), a C₃₋₁₁ cycloalkyl group, a 3 to 11-memberednon-aromatic heterocyclyl group, a phenyl group, a naphthyl group, a 5to 10-membered aromatic heterocyclyl group, a 8 to 11-membered partiallysaturated aromatic cyclic group or a 8 to 11-membered aromaticring-condensed alicyclic hydrocarbon group (the C₃₋₁₁ cycloalkyl group,the 3 to 11-membered non-aromatic heterocyclyl group, the phenyl group,the naphthyl group, the 5 to 10-membered aromatic heterocyclyl group,the 8 to 11-membered partially saturated aromatic cyclic group and the 8to 11-membered aromatic ring-condensed alicyclic hydrocarbon group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(1a) andthe substituent set V^(9a)).

Another preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-9):

andR^(2a) is a hydrogen atom.

Another preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by any of thefollowing formulae (XXVI^(a)-1) to (XXVI^(a)-5):

(wherein E^(1a) is an oxygen atom or a sulfur atom, and R^(12a) is aC₁₋₆ alkyl group or a C₁₋₆ haloalkyl group (the C₁₋₆ alkyl group and theC₁₋₆ haloalkyl group is substituted with one or two identical ordifferent substituents independently selected from the group consistingof hydroxy groups, amino groups, carboxy groups, carbamoyl groups,sulfamoyl groups, halogen atoms, cyano groups, nitro groups, C₁₋₆ alkoxygroups, C₁₋₆ haloalkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆haloalkylthio groups, C₁₋₆ alkylcarbonyl groups, C₁₋₆ haloalkylcarbonylgroups, C₁₋₆ alkylsulfonyl groups, C₁₋₆ haloalkylsulfonyl groups, C₁₋₆alkoxycarbonyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylaminogroups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonylgroups, C₁₋₆ alkylcarbonylamino groups, C₃₋₁₁ cycloalkyl groups, 3 to11-membered non-aromatic heterocyclyl groups, C₆₋₁₄ aryl groups and 5 to10-membered aromatic heterocyclyl groups (the C₃₋₁₁ cycloalkyl groups,the 3 to 11-membered non-aromatic heterocyclyl groups, the C₆₋₁₄ arylgroups and the 5 to 10-membered aromatic heterocyclyl groups areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(1a))), aC₃₋₁₁ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclylgroup, a C₆₋₁₄ aryl group or a 5 to 10-membered aromatic heterocyclylgroup (the C₃₋₁₁ cycloalkyl group, the 3 to 11-membered non-aromaticheterocyclyl group, the C₆₋₁₄ aryl group and the 5 to 10-memberedaromatic heterocyclyl group are unsubstituted and substituted with oneor more identical or different substituents independently selected fromthe substituent set V^(1a))), andR^(2a) is a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group(the C₁₋₆ alkyl group, the C₂₋₆ alkenyl group and the C₂₋₆ alkynyl groupare unsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(6a) andthe substituent set V^(9a)), a C₃₋₆ cycloalkyl group, a 3 to 11-memberednon-aromatic heterocyclyl group, a phenyl group, a naphthyl group or a 5to 10-membered aromatic heterocyclyl group (the C₃₋₆ cycloalkyl group,the 3 to 11-membered non-aromatic heterocyclyl group, the phenyl group,the naphthyl group and the 5 to 10-membered aromatic heterocyclyl groupare unsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(1a) andthe substituent set V^(9a)).

A more preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is a single bond, and R^(2a) is ahydrogen atom, a halogen atom, a C₃₋₆ cycloalkyl group, a phenyl groupor a 5 to 6-membered aromatic heterocyclyl group (the C₃₋₆ cycloalkylgroup, the phenyl group and the 5 to 6-membered aromatic heterocyclylgroup are unsubstituted or substituted with one or more identical ordifferent substituents independently selected from the substituent setV^(1a)).

Another more preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is a single bond, and R^(2a) is a3 to 11-membered non-aromatic heterocyclyl group (the 3 to 11-memberednon-aromatic heterocyclyl group is unsubstituted or substituted with oneor more identical or different substituents independently selected fromthe substituent set V^(1a)).

Another more preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is a single bond, and R^(2a) is aC₃₋₆ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclylgroup, a phenyl group or a 5 to 6-membered aromatic heterocyclyl group(the C₃₋₆ cycloalkyl group, the 3 to 11-membered non-aromaticheterocyclyl group, the phenyl group and the 5 to 6-membered aromaticheterocyclyl group are substituted with identical or different one, twoor three substituents independently selected from the group consistingof C₁₋₆ alkyl groups, C₁₋₆ alkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆alkylsulfonyl groups, C₁₋₆ alkylcarbonyl groups (the C₁₋₆ alkyl groups,the C₁₋₆ alkoxy groups, the C₁₋₆ alkylthio groups, the C₁₋₆alkylsulfonyl groups and the C₁₋₆ alkylcarbonyl groups are substitutedwith a substituent selected from the group consisting of a hydroxygroup, a cyano group, a C₁₋₆ alkoxy group and a C₁₋₆ alkoxycarbonylaminogroup), C₁₋₆ alkoxycarbonyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆alkylamino groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆alkylaminocarbonyl groups, C₁₋₆ alkylcarbonylamino groups, (the C₁₋₆alkoxycarbonyl groups, the mono-C₁₋₆ alkylamino groups, the di-C₁₋₆alkylamino groups, the mono-C₁₋₆ alkylaminocarbonyl groups, the di-C₁₋₆alkylaminocarbonyl groups and the C₁₋₆ alkylcarbonylamino groups aresubstituted with one or more identical or different halogen atomsindependently selected from the group consisting of fluorine atoms,chlorine atoms, bromine atoms and iodine atoms or with a hydroxy groupor a cyano group), mono-alkylaminosulfonyl groups, di-C₁₋₆alkylaminosulfonyl groups, C₁₋₆ alkylsulfonylamino groups, C₁₋₆alkoxycarbonylamino groups (the mono-C₁₋₆ alkylaminosulfonyl groups, thedi-C₁₋₆ alkylaminosulfonyl groups, the C₁₋₆ alkylsulfonylamino groupsand the C₁₋₆ alkoxycarbonylamino groups are unsubstituted or substitutedwith one or more identical or different halogen atoms independentlyselected from the group consisting of fluorine atoms, chlorine atoms,bromine atoms and iodine atoms), phenyl groups and 5 to 6-memberedaromatic heterocyclyl groups (the phenyl groups and the 5 to 6-memberedaromatic heterocyclyl groups are unsubstituted or substituted with oneor two identical or different substituents independently selected fromthe substituent set V^(1a))).

Another more preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is a single bond, and R^(2a) is aC₃₋₆ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclylgroup, a phenyl group or a 5 to 6-membered aromatic heterocyclyl group(the C₃₋₆ cycloalkyl group, the 3 to 11-membered non-aromaticheterocyclyl group, the phenyl group and the 5 to 6-membered aromaticheterocyclyl group are substituted with a substituent selected from thegroup consisting of a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group (the C₁₋₆alkyl group and the C₁₋₆ alkoxy group are substituted with a hydroxygroup or a cyano group), a mono-C₁₋₆ alkylamino group, a di-C₁₋₆alkylamino group, a mono-C₁₋₆ alkylaminocarbonyl group, a C₁₋₆alkylcarbonylamino group (the mono-C₁₋₆ alkylamino group, the di-C₁₋₆alkylamino group, the mono-C₁₋₆ alkylaminocarbonyl group and the C₁₋₆alkylcarbonylamino group are substituted with one or more identical ordifferent substituents independently selected from the group consistingof halogen atoms, hydroxy groups and cyano groups), a phenyl group, a 5to 6-membered aromatic heterocyclyl group (the phenyl group and the 5 to6-membered aromatic heterocyclyl group are unsubstituted or substitutedwith one or two identical or different substituents independentlyselected from the group consisting of halogen atoms, cyano groups, C₁₋₆alkyl groups and C₁₋₆ haloalkyl groups), a mono-C₁₋₆ alkylaminosulfonylgroup, a di-C₁₋₆ alkylaminosulfonyl group, a C₁₋₆ alkylsulfonylaminogroup and a C₁₋₆ alkoxycarbonylamino group (the mono-C₁₋₆alkylaminosulfonyl group, the di-C₁₋₆ alkylaminosulfonyl group, the C₁₋₆alkylsulfonylamino group and the C₁₋₆ alkoxycarbonylamino group areunsubstituted or substituted with one or more identical or differenthalogen atoms independently selected from the group consisting offluorine atoms, chlorine atoms, bromine atoms and iodine atoms) and withone or more identical or different substituents independently selectedfrom the group consisting of hydroxy groups, halogen atoms, cyanogroups, C₁₋₆ alkyl groups, C₁₋₆ haloalkyl groups, C₁₋₆ alkoxy groups,C₁₋₆ haloalkoxy groups, C₁₋₆ alkylsulfonyl groups and C₁₋₆haloalkylsulfonyl groups).

Another more preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is a single bond, and R^(2a) isan azido group.

Another more preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is a single bond, and R^(2a) is a8 to 11-membered partially saturated aromatic cyclic group (the 8 to11-membered partially saturated aromatic cyclic group is unsubstitutedor substituted with one or two identical or different halogen atomsindependently selected from the group consisting of fluorine atoms,chlorine atoms, bromine atoms and iodine atoms).

Another more preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by any of thefollowing formulae (IX^(a)-1) to (IX^(a)-9):

(wherein R^(12a) is a hydrogen atom or a C₁₋₃ alkyl group), and R^(2a)is a hydrogen atom, a C₁₋₆ alkyl group or a C₁₋₆ haloalkyl group (theC₁₋₆ alkyl group and the C₁₋₆ haloalkyl group are unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of hydroxy groups,amino groups, carbamoyl groups, sulfamoyl groups, tetrazolyl groups,cyano groups, nitro groups, C₃₋₆ cycloalkyl groups, C₁₋₃ alkoxy groups,C₁₋₆ haloalkoxy groups, C₁₋₃ alkylsulfonyl groups, C₁₋₃haloalkylsulfonyl groups, 4 to 7-membered non-aromatic heterocyclylgroups, phenyl groups and 5 to 6-membered aromatic heterocyclyl groups).

Another more preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by any of thefollowing formulae (IX^(a)-1) to (IX^(a)-9):

(wherein R^(12a) is a hydrogen atom, a C₁₋₃ alkyl group or a C₁₋₃haloalkyl group), and R^(2a) is a hydrogen atom, a C₁₋₆ alkyl group, aC₁₋₆ haloalkyl group (the C₁₋₆ alkyl group and the C₁₋₆ haloalkyl groupare unsubstituted or substituted with one, two or three identical ordifferent substituents independently selected from the group consistingof hydroxy groups, amino groups, carbamoyl groups, sulfamoyl groups,cyano groups, nitro groups, C₁₋₆ alkoxy groups, C₁₋₆ haloalkoxy groups,C₁₋₆ alkylsulfonyl groups, C₁₋₆ haloalkylsulfonyl groups, mono-C₁₋₆alkylamino groups, di-C₁₋₆ alkylamino groups, mono-C₁₋₆alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups (themono-C₁₋₆ alkylamino groups, the di-C₁₋₆ alkylamino groups, themono-C₁₋₆ alkylaminocarbonyl groups and the di-C₁₋₆ alkylaminocarbonylgroups are unsubstituted or substituted with one or more identical ordifferent halogen atoms independently selected from the group consistingof fluorine atoms, chlorine atoms, bromine atoms and iodine atoms), C₃₋₆cycloalkyl groups, 3 to 11-membered non-aromatic heterocyclyl groups,phenyl groups and 5 to 10-membered aromatic heterocyclyl groups (theC₃₋₆ cycloalkyl groups, the 3 to 11-membered non-aromatic heterocyclylgroups, the phenyl groups and the 5 to 10-membered aromatic heterocyclylgroups are unsubstituted or substituted with identical or different oneor more substituents independently selected from the group consisting ofhydroxy groups, amino groups, halogen atoms, cyano groups, carbamoylgroups, C₁₋₆ alkoxy groups, C₁₋₆ haloalkoxy groups, C₁₋₆ alkylthiogroups, C₁₋₆ haloalkylthio groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆haloalkylsulfonyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆alkylamino groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆alkylaminocarbonyl groups, C₁₋₆ alkylcarbonylamino groups, C₁₋₆alkoxycarbonyl groups (the mono-C₁₋₆ alkylamino groups, the di-C₁₋₆alkylamino groups, the mono-C₁₋₆ alkylaminocarbonyl groups, the di-C₁₋₆alkylaminocarbonyl groups, the C₁₋₆ alkylcarbonylamino groups and theC₁₋₆ alkoxycarbonyl groups are unsubstituted or substituted with one ormore identical or different halogen atoms independently selected fromthe group consisting of fluorine atoms, chlorine atoms, bromine atomsand iodine atoms), 4 to 7-membered non-aromatic heterocyclyl groups,phenyl groups and 5 to 6-membered aromatic heterocyclyl groups)), a C₃₋₆cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclyl group, aphenyl group or a 5 to 10-membered aromatic heterocyclyl group (the C₃₋₆cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclyl group,the phenyl group and the 5 to 10-membered aromatic heterocyclyl groupare unsubstituted or substituted with identical or different one or moresubstituents independently selected from the group consisting of hydroxygroups, amino groups, halogen atoms, cyano groups, carbamoyl groups,C₁₋₆ alkyl groups (the C₁₋₆ alkyl groups are unsubstituted orsubstituted with a substituent selected from the group consisting of ahydroxy group, a cyano group and a C₁₋₃ alkoxy group), C₁₋₆ haloalkylgroups, C₁₋₆ alkoxy groups, C₁₋₆ haloalkoxy groups, C₁₋₆ alkylthiogroups, C₁₋₆ haloalkylthio groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆haloalkylsulfonyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆alkylamino groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆alkylaminocarbonyl groups, C₁₋₆ alkylcarbonylamino groups, C₁₋₆alkoxycarbonyl groups (the mono-C₁₋₆ alkylamino groups, the di-C₁₋₆alkylamino groups, the mono-C₁₋₆ alkylaminocarbonyl groups, the di-C₁₋₆alkylaminocarbonyl groups, the C₁₋₆ alkylcarbonylamino groups and theC₁₋₆ alkoxycarbonyl groups are unsubstituted or substituted with one ormore identical or different halogen atoms independently selected fromthe group consisting of fluorine atoms, chlorine atoms, bromine atomsand iodine atoms), 4 to 7-membered non-aromatic heterocyclyl groups,phenyl groups and 5 to 6-membered aromatic heterocyclyl groups (thephenyl groups and the 5 to 6-membered aromatic heterocyclyl groups areunsubstituted or substituted with one or two identical or differentsubstituents independently selected from the group consisting of halogenatoms, cyano groups and C₁₋₃ haloalkyl groups)).

Another more preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by any of thefollowing formulae (XVII^(a)-1) to (XVII^(a)-3):

andR^(2a) is a hydrogen atom or a C₁₋₆ alkyl group.

Another more preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by the formula(XVIII^(a)):

(wherein R^(12a) is a hydrogen atom), and R^(2a) is a C₁₋₆ alkyl group(the C₁₋₆ alkyl group is, unsubstituted or substituted with a phenylgroup).

Another more preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by any of thefollowing formulae (IX^(a)-1) to (IX^(a)-9):

(wherein R^(12a) is a hydrogen atom, a C₁₋₃ alkyl group or a C₁₋₃haloalkyl group), and R^(2a) is a C₁₋₆ alkyl group, a C₁₋₆ haloalkylgroup (the C₁₋₆ alkyl group and the C₁₋₆ haloalkyl group are substitutedwith a substituent selected from the group consisting of a C₃₋₆cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclyl group, aphenyl group and a 5 to 10-membered aromatic heterocyclyl group (theC₃₋₆ cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclylgroup, the phenyl group and the 5 to 10-membered aromatic heterocyclylgroup are substituted with one or two identical or differentsubstituents independently selected from the group consisting of C₁₋₆alkyl groups (the C₁₋₆ alkyl groups are unsubstituted or substitutedwith a hydroxy group or a cyano group) and C₁₋₆ haloalkyl groups)) or aC₂₋₆ alkynyl group.

Another more preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by any of thefollowing formulae (IX^(a)-1) to (IX^(a)-9):

(wherein R^(12a) is a hydrogen atom, a C₁₋₃ alkyl group or a C₁₋₃haloalkyl group), and R^(2a) is a C₁₋₆ alkyl group or a C₁₋₆ haloalkylgroup (the C₁₋₆ alkyl group and the C₁₋₆ haloalkyl group are substitutedwith a substituent selected from the group consisting of a C₃₋₆cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclyl group, aphenyl group and a 5 to 10-membered aromatic heterocyclyl group (theC₃₋₆ cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclylgroup, the phenyl group and the 5 to 10-membered aromatic heterocyclylgroup are substituted with one or two identical or differentsubstituents independently selected from the group consisting of C₁₋₆alkyl groups and C₁₋₆ haloalkyl groups and with one or two identical ordifferent substituents independently selected from the group consistingof hydroxy groups, amino groups, halogen atoms, cyano groups, C₁₋₆alkoxy groups, C₁₋₆ haloalkoxy groups, mono-C₁₋₆ alkylamino groups,di-C₁₋₆ alkylamino groups, C₁₋₆ alkylthio groups, C₁₋₆ haloalkylthiogroups, C₁₋₆ alkylsulfonyl groups, C₁₋₆ haloalkylsulfonyl groups, C₃₋₆cycloalkyl groups, 4 to 7-membered non-aromatic heterocyclyl groups,phenyl groups and 5 to 6-membered aromatic heterocyclyl groups)).

Another more preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by the formula(XVI^(a)):

(wherein R^(12a) is a hydrogen atom), and R^(2a) is a 8 to 11-memberedpartially saturated aromatic cyclic group or a 8 to 11-membered aromaticring-condensed alicyclic hydrocarbon group (the 8 to 11-memberedpartially saturated aromatic cyclic group and the 8 to 11-memberedaromatic ring-condensed alicyclic hydrocarbon group are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the group consisting of halogen atoms andhydroxy groups).

Another more preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-10):

(wherein E^(1a) is NR^(11a) (wherein R^(11a) is a hydroxy group)), andR^(2a) is a hydrogen atom.

Another more preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by any of thefollowing formulae (XXVI^(a)-1) to (XXVI^(a)-5):

(wherein E^(1a) is an oxygen atom, and R^(12a) is a C₁₋₆ alkyl group(the C₁₋₆ alkyl group is substituted with a substituent selected fromthe group consisting of a hydroxy group, a cyano group, a C₁₋₃ alkoxygroup, a C₃₋₆ cycloalkyl group, a 4 to 7-membered non-aromaticheterocyclyl group, a phenyl group and a 5 to 6-membered aromaticheterocyclyl group (the C₃₋₆ cycloalkyl group, the 4 to 7-memberednon-aromatic heterocyclyl group, the phenyl group and the 5 to6-membered aromatic heterocyclyl group are unsubstituted or substitutedwith a substituent selected from the group consisting of a hydroxygroup, a halogen atom, a cyano group, a C₁₋₃ alkyl group, a C₁₋₃haloalkyl group and a C₁₋₃ alkoxy group)), a C₃₋₆ cycloalkyl group, a 4to 7-membered non-aromatic heterocyclyl group, a phenyl group or a 5 to6-membered aromatic heterocyclyl group (the C₃₋₆ cycloalkyl group, the 4to 7-membered non-aromatic heterocyclyl group, the phenyl group and the5 to 6-membered aromatic heterocyclyl group are unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of hydroxy groups,halogen atoms, cyano groups, C₁₋₃ alkyl groups, C₁₋₃ haloalkyl groupsand C₁₋₃ alkoxy groups)), and R^(2a) is a C₁₋₆ alkyl group, a C₁₋₆haloalkyl group (the C₁₋₆ alkyl group and the C₁₋₆ haloalkyl group areunsubstituted or substituted with one or two identical or differentsubstituents independently selected from the group consisting of hydroxygroups, cyano groups, C₁₋₃ alkoxy groups, mono-C₁₋₆ alkylaminocarbonylgroups, (the mono-C₁₋₆ alkylaminocarbonyl groups are unsubstituted orsubstituted with one or more identical or different halogen atomsindependently selected from the group consisting of fluorine atoms,chlorine atoms, bromine atoms and iodine atoms), C₃₋₆ cycloalkyl groups,4 to 7-membered non-aromatic heterocyclyl groups, phenyl groups and 5 to6-membered aromatic heterocyclyl groups (the C₃₋₆ cycloalkyl groups, the4 to 7-membered non-aromatic heterocyclyl groups, the phenyl groups andthe 5 to 6-membered aromatic heterocyclyl groups are unsubstituted orsubstituted with identical or different one or two substituentsindependently selected from the group consisting of hydroxy groups,halogen atoms, cyano groups, carbamoyl groups, C₁₋₆ alkyl groups, C₁₋₆haloalkyl groups, C₁₋₆ alkoxy groups, C₁₋₆ haloalkoxy groups, mono-C₁₋₆alkylamino groups and di-C₁₋₆ alkylamino groups)), a C₂₋₆ alkynyl group,a C₃₋₆ cycloalkyl group, a 4 to 7-membered non-aromatic heterocyclylgroup, a phenyl group or a 5 to 6-membered aromatic heterocyclyl group(the C₃₋₆ cycloalkyl group, the 4 to 7-membered non-aromaticheterocyclyl group, the phenyl group and the 5 to 6-membered aromaticheterocyclyl group are unsubstituted or substituted with one, two orthree identical or different substituents independently selected fromthe group consisting of hydroxy groups, halogen atoms, cyano groups,carbamoyl groups, C₁₋₆ alkyl groups, C₁₋₆ haloalkyl groups, C₁₋₆ alkoxygroups, C₁₋₆ halo alkoxy groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆alkylamino groups, phenyl groups and 5 to 6-membered aromaticheterocyclyl group).

A further preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is a single bond, and R^(2a) is ahydrogen atom, a halogen atom, a C₃₋₆ cycloalkyl group, a phenyl groupor a 5 to 6-membered aromatic heterocyclyl group (the C₃₋₆ cycloalkylgroup, the phenyl group and the 5 to 6-membered aromatic heterocyclylgroup are unsubstituted or substituted with identical or different one,two or three substituents independently selected from the groupconsisting of hydroxy groups, amino groups, halogen atoms, cyano groups,nitro groups, carbamoyl groups, sulfamoyl groups, C₁₋₆ alkyl groups,C₁₋₆ haloalkyl groups, C₁₋₆ alkoxy groups, C₁₋₆ haloalkoxy groups,mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups, C₁₋₆ alkylthiogroups, C₁₋₆ haloalkylthio groups, C₁₋₆ alkylcarbonyl groups, C₁₋₆haloalkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆haloalkylsulfonyl groups, carboxy groups, C₁₋₆ alkoxycarbonyl groups,mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups,C₁₋₆ alkylcarbonylamino groups, C₃₋₆ cycloalkyl groups and 4 to7-membered non-aromatic heterocyclyl groups).

Another further preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is a single bond, and R^(2a) is a3 to 11-membered non-aromatic heterocyclyl group (the 3 to 11-memberednon-aromatic heterocyclyl group is unsubstituted or substituted withone, two or three identical or different substituents independentlyselected from the group consisting of hydroxy groups, amino groups,halogen atoms, cyano groups, nitro groups, carbamoyl groups, sulfamoylgroups, C₁₋₆ alkyl groups, C₁₋₆ haloalkyl groups, C₁₋₆ alkoxy groups,C₁₋₆ haloalkoxy groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylaminogroups, C₁₋₆ alkylthio groups, C₁₋₆ haloalkylthio groups, C₁₋₆alkylcarbonyl groups, C₁₋₆ haloalkylcarbonyl groups, C₁₋₆ alkylsulfonylgroups, C₁₋₆ haloalkylsulfonyl groups, carboxy groups, C₁₋₆alkoxycarbonyl groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆alkylaminocarbonyl groups, C₁₋₆ alkylcarbonylamino groups, C₃₋₆cycloalkyl groups and 4 to 7-membered non-aromatic heterocyclyl groups).

Another further preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is a single bond, and R^(2a) is a4 to 7-membered non-aromatic heterocyclyl group, a phenyl group or a 5to 6-membered aromatic heterocyclyl group (the 4 to 7-memberednon-aromatic heterocyclyl group, the phenyl group and the 5 to6-membered aromatic heterocyclyl group are substituted with a C₁₋₆ alkylgroup, a C₁₋₆ alkoxy group (the C₁₋₆ alkyl group and the C₁₋₆ alkoxygroup are substituted with a substituent selected from the groupconsisting of a hydroxy group, a cyano group and a C₁₋₆alkoxycarbonylamino group), a mono-C₁₋₆ alkylamino group, a di-C₁₋₆alkylamino group, a mono-C₁₋₆ alkylaminocarbonyl group, a C₁₋₆alkylcarbonylamino group (the mono-C₁₋₆ alkylamino group, the di-C₁₋₆alkylamino group, the mono-C₁₋₆ alkylaminocarbonyl group and the C₁₋₆alkylcarbonylamino group are substituted with one or more identical ordifferent halogen atoms independently selected from the group consistingof fluorine atoms, chlorine atoms, bromine atoms and iodine atoms orwith a hydroxy group or a cyano group), a C₁₋₆ alkoxycarbonyamino group,a phenyl group and a 5 to 6-membered aromatic heterocyclyl group (thephenyl group and the 5 to 6-membered aromatic heterocyclyl group areunsubstituted or substituted with one or two identical or differentsubstituents independently selected from the group consisting of halogenatoms, cyano groups, C₁₋₃ alkyl groups and C₁₋₃ haloalkyl groups)).

Another further preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is a single bond, R^(2a) is a 3to 11-membered non-aromatic heterocyclyl group (the 3 to 11-memberednon-aromatic heterocyclyl group is substituted with a di-C₁₋₃alkylaminosulfonyl group).

Another further preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is a single bond, R^(2a) is a 4to 7-membered non-aromatic heterocyclyl group (the 4 to 7-memberednon-aromatic heterocyclyl group is substituted with a phenyl group (thephenyl group is unsubstituted or substituted with one or two identicalor different substituents independently selected from the groupconsisting of halogen atoms, C₁₋₃ alkyl groups and C₁₋₃ haloalkylgroups) and with a substituent selected from the group consisting of ahydroxy group, a halogen atom, a cyano group, a C₁₋₃ alkyl group and aC₁₋₃ haloalkyl group).

Another further preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by any of thefollowing formulae (XX^(a)-1) to (XX^(a)-3):

(wherein R^(12a) is a hydrogen atom or a C₁₋₃ alkyl group), and R^(2a)is a hydrogen atom, a C₁₋₆ alkyl group or a C₁₋₆ haloalkyl group (theC₁₋₆ alkyl group and the C₁₋₆ haloalkyl group are unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of hydroxy groups,cyano groups, C₁₋₃ alkoxy groups, C₃₋₆ cycloalkyl groups, 4 to7-membered non-aromatic heterocyclyl groups, phenyl groups and 5 to6-membered aromatic heterocyclyl groups).

Another further preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by any of thefollowing formulae (XXI^(a)-1) to (XXI^(a)-3):

and R^(2a) is a hydrogen atom or a C₁₋₆ alkyl group (the C₁₋₆ alkylgroup is unsubstituted or substituted with a phenyl groups).

Another further preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-4):

andR^(2a) is a C₁₋₃ haloalkyl group.

Another further preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by any of thefollowing formulae (XXVIII^(a)-1) to (XXVIII^(a)-3):

(wherein E^(1a) is an oxygen atom, and R^(12a) is a hydrogen atom or aC₁₋₃ alkyl group), and R^(2a) is a C₁₋₆ alkyl group (the C₁₋₆ alkylgroup is unsubstituted or substituted with a cyano group) or a C₁₋₆haloalkyl group.

Another further preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by any of thefollowing formulae (XX^(a)-1) to (XX^(a)-3):

(wherein R^(12a) is a hydrogen atom or a C₁₋₃ alkyl group), and R^(2a)is a C₁₋₆ alkyl group or a C₁₋₆ haloalkyl group (the C₁₋₆ alkyl groupand the C₁₋₆ haloalkyl group are substituted with a substituent selectedfrom the group consisting of a mono-C₁₋₆ alkylaminocarbonyl group (themono-C₁₋₆ alkylaminocarbonyl group is unsubstituted or substituted withone or more identical or different halogen atoms independently selectedfrom the group consisting of fluorine atoms, chlorine atoms, bromineatoms and iodine atoms), a C₃₋₆ cycloalkyl group, a 4 to 7-memberednon-aromatic heterocyclyl group, a phenyl group and a 5 to 6-memberedaromatic heterocyclyl group (the C₃₋₆ cycloalkyl group, the 4 to7-membered non-aromatic heterocyclyl group, the phenyl group and the 5to 6-membered aromatic heterocyclyl group are substituted with one ortwo identical or different substituents independently selected from thegroup consisting of hydroxy groups, amino groups, halogen atoms, cyanogroups, carbamoyl groups, C₁₋₆ alkoxy groups, C₁₋₆ haloalkoxy groups,mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups, C₁₋₆ alkylthiogroups, C₁₋₆ haloalkylthio groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆haloalkylsulfonyl groups, C₁₋₆ alkoxycarbonyl groups and phenyl groups(the phenyl groups are unsubstituted or substituted with one or twoidentical or different substituents independently selected from thegroup consisting of halogen atoms and C₁₋₃ haloalkyl groups))).

Another further preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by any of thefollowing formulae (XX^(a)-1) to (XX^(a)-3):

(wherein R^(12a) is a hydrogen atom or a C₁₋₃ alkyl group), and R^(2a)is a C₁₋₆ alkyl group or a C₁₋₆ haloalkyl group (the C₁₋₆ alkyl groupand the C₁₋₆ haloalkyl group are substituted with a substituent selectedfrom the group consisting of a C₃₋₆ cycloalkyl group, a 4 to 7-memberednon-aromatic heterocyclyl group, a phenyl group and a 5 to 6-memberedaromatic heterocyclyl group (the C₃₋₆ cycloalkyl group, the 4 to7-membered non-aromatic heterocyclyl group, the phenyl group and the 5to 6-membered aromatic heterocyclyl group are substituted with one ortwo identical or different substituents independently selected from thegroup consisting of hydroxy groups, amino groups, halogen atoms, cyanogroups, carbamoyl groups, C₁₋₆ alkoxy groups, C₁₋₆ haloalkoxy groups,mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups, C₁₋₆ alkylthiogroups, C₁₋₆ haloalkylthio groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆haloalkylsulfonyl groups and 4 to 7-membered non-aromatic heterocyclylgroups) and with a substituent selected from the group consisting of ahydroxy group and a cyano group).

Another further preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by any of thefollowing formulae (XXVII^(a)-1) to (XXVII^(a)-5):

(wherein R^(12a) is a hydrogen atom or a C₁₋₃ alkyl group), and R^(2a)is a C₃₋₆ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclylgroup, a phenyl group or a 5 to 10-membered aromatic heterocyclyl group(the C₃₋₆ cycloalkyl group, the 3 to 11-membered non-aromaticheterocyclyl group, the phenyl group and the 5 to 10-membered aromaticheterocyclyl group are unsubstituted or substituted with one or twoidentical or different substituents independently selected from thegroup consisting of hydroxy groups, amino groups, halogen atoms, cyanogroups, carbamoyl groups, C₁₋₆ alkyl groups (the C₁₋₆ alkyl groups areunsubstituted or substituted with a substituent selected from the groupconsisting of a hydroxy group, a cyano group and a C₁ alkoxy group),C₁₋₆ haloalkyl groups, C₁₋₆ alkoxy groups, C₁₋₆ haloalkoxy groups,mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups, C₁₋₆ alkylthiogroups, C₁₋₆ haloalkylthio groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆haloalkylsulfonyl groups, C₁₋₆ alkoxycarbonyl groups, 4 to 7-memberednon-aromatic heterocyclyl groups, phenyl groups and 5 to 6-memberedaromatic heterocyclyl groups (the phenyl groups and the 5 to 6-memberedaromatic heterocyclyl groups are unsubstituted or substituted with ahalogen atom)).

Another further preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by any of thefollowing formulae (XXVI^(a)-1) to (XXVI^(a)-5):

(wherein E^(1a) is an oxygen atom, and R^(12a) is a C₁₋₆ haloalkylgroup), and R^(2a) is a C₁₋₆ alkyl group (the C₁₋₆ alkyl group isunsubstituted or substituted with a substituent selected from the groupconsisting of a hydroxy group, a cyano group, a C₁₋₃ alkoxy group, aC₃₋₆ cycloalkyl group and a phenyl group) or a C₁₋₆ haloalkyl group.

Another further preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-5):

andR^(2a) is a C₁₋₃ alkyl group.

Another further preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-6):

andR^(2a) is a hydrogen atom.

Another further preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by the formula(XVIII^(a)):

(wherein R^(12a) is a hydrogen atom), and R^(2a) is a C₁₋₆ alkyl groupor a C₁₋₃ alkyl group (the C₁₋₃ alkyl group is substituted with a phenylgroup).

Another further preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-8):

andR^(2a) is a C₁₋₃ alkyl group.

Another further preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by any of thefollowing formulae (XX^(a)-1) to (XX^(a)-3):

(wherein R^(12a) is a hydrogen atom or a C₁₋₃ alkyl group), and R^(2a)is a C₁₋₃ alkyl group (the C₁₋₃ alkyl group is substituted with asubstituent selected from the group consisting of a C₃₋₆ cycloalkylgroup, a 4 to 7-membered non-aromatic heterocyclyl group, a phenyl groupand a 5 to 6-membered aromatic heterocyclyl group (the C₃₋₆ cycloalkylgroup, the 4 to 7-membered non-aromatic heterocyclyl group, the phenylgroup and the 5 to 6-membered aromatic heterocyclyl group aresubstituted with a C₁₋₃ alkyl group or a C₁₋₃ haloalkyl group)) or aC₂₋₆ alkynyl group.

Another further preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by any of thefollowing formulae (XX^(a)-1) to (XX^(a)-3):

(wherein R^(12a) is a hydrogen atom or a C₁₋₃ alkyl group), and R^(2a)is a C₁₋₃ alkyl group (the C₁₋₃ alkyl group is substituted with asubstituent selected from the group consisting of a phenyl group and a 5to 6-membered aromatic heterocyclyl group (the phenyl group and the 5 to6-membered aromatic heterocyclyl group are substituted with a C₁₋₃ alkylgroup or a C₁₋₃ haloalkyl group and with a substituent selected from thegroup consisting of a halogen atom, a cyano group, a C₁₋₃ alkoxy group,a C₁₋₃ haloalkoxy group and a C₁₋₃ alkylsulfonyl group)).

Another further preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by the formula(XVI^(a)):

(wherein R^(12a) is a hydrogen atom), and R^(2a) is a 8 to 11-memberedpartially saturated aromatic cyclic group or a 8 to 11-membered aromaticring-condensed alicyclic hydrocarbon group (the 8 to 11-memberedpartially saturated aromatic cyclic group and the 8 to 11-memberedaromatic ring-condensed alicyclic hydrocarbon group are unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of halogen atoms andhydroxy groups).

Another further preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is represented by any of thefollowing formulae (XXVI^(a)-1) to (XXVI^(a)-5):

(wherein E^(1a) is an oxygen atom, and R^(12a) is a C₁₋₃ alkyl group(the C₁₋₃ alkyl group is substituted with a substituent selected fromthe group consisting of a cyano group, a hydroxy group, a C₁₋₃ alkoxygroup, a C₃₋₆ cycloalkyl group, a phenyl group and a 5 to 6-memberedaromatic heterocyclyl group (the 5 to 6-membered aromatic heterocyclylgroup is unsubstituted or substituted with a C₁₋₃ alkyl group)), a C₃₋₆cycloalkyl group or a phenyl group (the phenyl group is unsubstituted orsubstituted with a halogen or a cyano group)), andR^(2a) is a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group (the C₁₋₃ alkylgroup and the C₁₋₃ haloalkyl group are unsubstituted or substituted withone or two identical or different substituents independently selectedfrom the group consisting of hydroxy groups, cyano groups, C₁₋₃ alkoxygroups, C₃₋₆ cycloalkyl groups, phenyl groups and 5 to 6-memberedaromatic heterocyclyl groups).

A particularly preferred embodiment of the substituent L^(3a) and thesubstituent R^(2a) is such that L^(3a) is a single bond, and R^(2a) is ahydrogen atom or a halogen atom.

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is a single bond, and R^(2a)is a C₃₋₆ cycloalkyl group (the C₃₋₆ cycloalkyl group is unsubstitutedor substituted with a C₁₋₃ haloalkyl group).

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is a single bond, and R^(2a)is a phenyl group or a 5 to 6-membered aromatic heterocyclyl group (thephenyl group and the 5 to 6-membered aromatic heterocyclyl group areunsubstituted or substituted with one, two or three identical ordifferent substituents independently selected from the group consistingof halogen atoms, cyano groups, carbamoyl groups, C₁₋₃ alkyl groups,C₁₋₃ alkoxy groups, C₁₋₃ alkylthio groups, C₁₋₃ alkylsulfonyl groups,C₁₋₃ haloalkyl groups, C₁₋₃ haloalkoxy groups, C₁₋₃ haloalkylthio groupsand 4 to 7-membered non-aromatic heterocyclyl groups).

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is a single bond, and R^(2a)is a 4 to 7-membered non-aromatic heterocyclyl group (the 4 to7-membered non-aromatic heterocyclyl group is unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of cyano groups,halogen atoms, C₁₋₃ alkyl groups, C₁₋₃ haloalkyl groups, hydroxy groups,di-C₁₋₃ alkylamino groups, carboxy groups, carbamoyl groups, C₁₋₃haloalkoxy groups, C₁₋₃ alkylcarbonylamino groups and 4 to 7-memberednon-aromatic heterocyclyl groups).

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is a single bond, and R^(2a)is a phenyl group (the phenyl group is substituted with a substituentselected from the group consisting of a C₁₋₃ alkoxy group, a di-C₁₋₃alkylamino group (the C₁₋₃ alkoxy group and the di-C₁₋₃ alkylamino groupare substituted with a hydroxy group or a cyano group) and a 5 to6-membered aromatic heterocyclyl group).

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is a single bond, and R^(2a)is a 5 to 6-membered aromatic heterocyclyl group (the 5 to 6-memberedaromatic heterocyclyl group is substituted with a C₁₋₃ alkyl group (theC₁₋₃ alkyl group is substituted with a hydroxy group).

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is a single bond, and R^(2a)is a 4 to 7-membered non-aromatic heterocyclyl group (the 4 to7-membered non-aromatic heterocyclyl group is substituted with asubstituent selected from the group consisting of a C₁₋₆ alkyl group(the C₁₋₆ alkyl group is substituted with a substituent selected fromthe group consisting of a hydroxy group, a cyano group and a C₁₋₆alkoxycarbonylamino group), a mono-C₁₋₃ alkylaminocarbonyl group, a C₁₋₃alkylcarbonylamino group (the mono-C₁₋₃ alkylaminocarbonyl group and theC₁₋₃ alkylcarbonylamino group are substituted with one or more identicalor different halogen atoms independently selected from the groupconsisting of fluorine atoms, chlorine atoms, bromine atoms and iodineatoms) and a C₁₋₆ alkoxycarbonylamino group).

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is a single bond, and R^(2a)is a 4 to 7-membered non-aromatic heterocyclyl group (the 4 to7-membered non-aromatic heterocyclyl group is substituted with a phenylgroup (the phenyl group is unsubstituted or substituted with one or twoidentical or different substituents independently selected from thegroup consisting of halogen atoms and C₁₋₃ haloalkyl groups) and with ahydroxy group or a cyano group).

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-1):

andR^(2a) is a methyl group (the methyl group is unsubstituted orsubstituted with a cyano group).

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-1):

andR^(2a) is a hydrogen atom or a C₁₋₃ haloalkyl group.

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-1):

andR^(2a) is a 4 to 7-membered non-aromatic heterocyclyl group or a phenylgroup (the 4 to 7-membered non-aromatic heterocyclyl group and thephenyl group are unsubstituted or substituted with a substituentselected from the group consisting of a hydroxy group, a cyano group, ahalogen atom and a C₁₋₃ haloalkyl group).

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-7):

(wherein R^(12a) is a hydrogen atom), and R^(2a) is a hydrogen atom, aC₁₋₃ alkyl group or a C₁₋₃ haloalkyl group (the C₁₋₃ alkyl group and thea C₁₋₃ haloalkyl group are unsubstituted or substituted with one or twoidentical or different substituents independently selected from thegroup consisting of hydroxy groups, cyano groups and phenyl groups).

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-7):

(wherein R^(12a) is a hydrogen atom), and R^(2a) is a C₁₋₃ alkyl group(the C₁₋₃ alkyl group is substituted with a phenyl group (the phenylgroup is substituted with a halogen atom or a cyano group)).

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-7):

(wherein R^(12a) is a hydrogen atom), and R^(2a) is a C₁₋₃ haloalkylgroup (the C₁₋₃ haloalkyl group is substituted with a phenyl group (thephenyl group is substituted with a halogen atom) and with a hydroxygroup).

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-7):

(wherein R^(12a) is a hydrogen atom), and R^(2a) is a C₃₋₆ cycloalkylgroup, a phenyl group or a 5 to 6-membered aromatic heterocyclyl group(the C₃₋₆ cycloalkyl group, the phenyl group and the 5 to 6-memberedaromatic heterocyclyl group are unsubstituted or substituted with asubstituent selected from the group consisting of a C₁₋₃ alkyl group, aC₁₋₃ haloalkyl group and a halogen atom).

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(XVI^(a)):

(wherein R^(12a) is a hydrogen atom or a C₁₋₃ alkyl group), and R^(2a)is a hydrogen atom, a C₁₋₆ alkyl group (the C₁₋₆ alkyl group isunsubstituted or substituted with a substituent selected from the groupconsisting of a hydroxy group, a cyano group, a C₁₋₃ alkoxy group, aC₃₋₆ cycloalkyl group, a 4 to 7-membered non-aromatic heterocyclylgroup, a phenyl group and a 5 to 6-membered aromatic heterocyclyl group)or a C₁₋₆ haloalkyl group (the C₁₋₆ haloalkyl group is unsubstituted orsubstituted with a hydroxy group).

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(XVI^(a)):

(wherein R^(12a) is a C₁₋₃ haloalkyl group), and R^(2a) is a C₁₋₃ alkylgroup (the C₁₋₃ alkyl group is substituted with a C₃₋₆ cycloalkylgroup).

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(XVI^(a)):

(wherein R^(12a) is a hydrogen atom), and R^(2a) is a C₁₋₃ alkyl groupor a C₁₋₃ haloalkyl group (the C₁₋₃ alkyl group and the C₁₋₃ haloalkylgroup are substituted with a hydroxy group and with a phenyl group or a5 to 6-membered aromatic heterocyclyl group).

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(XVI^(a)):

(wherein R^(12a) is a hydrogen atom or a C₁₋₃ alkyl group), and R^(2a)is a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is substituted with a phenylgroup or a 5 to 6-membered aromatic heterocyclyl group (the phenyl groupand the 5 to 6-membered aromatic heterocyclyl group are substituted withone or two identical or different substituents independently selectedfrom the group consisting of halogen atoms, cyano groups, C₁₋₃ alkoxygroups, C₁₋₃ haloalkoxy groups and C₁₋₃ alkylsulfonyl groups)).

Another particularly preferred embodiment of the substituent L^(2a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(XVI^(a)):

(wherein R^(12a) is a hydrogen atom), and R^(2a) is a C₁₋₆ alkyl group(the C₁₋₆ alkyl group is substituted with a C₃₋₆ cycloalkyl group or a 4to 7-membered non-aromatic heterocyclyl group (the C₃₋₆ cycloalkyl groupand the 4 to 7-membered non-aromatic heterocyclyl group are substitutedwith a substituent selected from the group consisting of a hydroxygroup, a C₁₋₆ alkoxycarbonyl group and a phenyl group (the phenyl groupis unsubstituted or substituted with a halogen atom))).

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(XVI^(a)):

(wherein R^(12a) is a hydrogen atom), and R^(2a) is a C₁₋₃ alkyl groupor a C₁₋₃ haloalkyl group (the C₁₋₃ alkyl group and the C₁₋₃ haloalkylgroup are substituted with a phenyl group or a 5 to 6-membered aromaticheterocyclyl group (the phenyl group and the 5 to 6-membered aromaticheterocyclyl group are substituted with one or two identical ordifferent substituents independently selected from the group consistingof halogen atoms, C₁₋₃ alkoxy groups, C₁₋₃ haloalkoxy groups and C₁₋₃alkylthio groups) and with a hydroxy group).

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(XVI^(a)):

(wherein R^(12a) is a hydrogen atom or a C₁₋₃ alkyl group), and R^(2a)is a C₃₋₆ cycloalkyl group, a 4 to 7-membered non-aromatic heterocyclylgroup (the C₃₋₆ cycloalkyl group and the 4 to 7-membered non-aromaticheterocyclyl group are unsubstituted or substituted with one or twoidentical or different substituents independently selected from thegroup consisting of hydroxy groups, C₁₋₃ alkyl groups (the C₁₋₃ alkylgroups are unsubstituted or substituted with a substituent selected fromthe group consisting of a hydroxy group, a cyano group and a C₁₋₃ alkoxygroup), C₁₋₃ haloalkyl groups, C₁₋₆ alkoxycarbonyl groups and phenylgroups (the phenyl groups are unsubstituted or substituted with ahalogen atom), a phenyl group or a 5 to 10-membered aromaticheterocyclyl group (the phenyl group and the 5 to 10-membered aromaticheterocyclyl group are unsubstituted or substituted with identical ordifferent one, two or three substituents independently selected from thegroup consisting of halogen atoms, cyano groups, C₁₋₃ alkyl groups, C₁₋₃haloalkyl groups, C₁₋₃ alkoxy groups, C₁₋₃ haloalkoxy groups, C₁₋₃haloalkylsulfonyl groups and 4 to 7-membered non-aromatic heterocyclylgroups).

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-2):

andR^(2a) is a methyl group (the methyl group is unsubstituted orsubstituted with a phenyl group).

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-2):

andR^(2a) is a hydrogen atom or a t-butyl group.

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-3):

andR^(2a) is a hydrogen atom.

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-3):

andR^(2a) is a C₁₋₃ alkyl group.

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-4):

andR^(2a) is a C₁₋₃ alkyl group.

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-4):

andR^(2a) is a C₃₋₆ cycloalkyl group or a phenyl group (the phenyl group isunsubstituted or substituted with a halogen atom).

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-11):

(wherein R^(12a) is a hydrogen atom or a C₁₋₃ alkyl group), and R^(2a)is a C₁₋₃ alkyl group (the C₁₋₃ alkyl group is unsubstituted orsubstituted with a cyano group) or a C₁₋₃ haloalkyl group.

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-11):

(wherein R^(12a) is a C₁₋₃ haloalkyl group), and R^(2a) is a C₁₋₃ alkylgroup (the C₁₋₃ alkyl group is unsubstituted or substituted with a cyanogroup) or a C₁₋₃ haloalkyl group.

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-12):

(wherein R^(12a) is a hydrogen atom or a C₁₋₃ alkyl group), and R^(2a)is a C₁₋₃ alkyl group (the C₁₋₃ alkyl group is unsubstituted orsubstituted with a cyano group) or a C₁₋₃ haloalkyl group.

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-12):

(wherein R^(12a) is a hydrogen atom), and R^(2a) is a C₃₋₆ cycloalkylgroup.

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-13):

(wherein R^(12a) is a hydrogen atom), and R^(2a) is a C₁₋₃ alkyl group.

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-5):

andR^(2a) is a methyl group.

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(XVIII^(a)):

(wherein R^(12a) is a hydrogen atom), and R^(2a) is a methyl group (themethyl group is substituted with a phenyl group) or a t-butyl group.

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-8):

andR^(2a) is a methyl group.

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-7):

(wherein R^(12a) is a hydrogen atom), and R^(2a) is a C₁₋₃ alkyl group(the C₁₋₃ alkyl group is substituted with a 5 to 6-membered aromaticheterocyclyl group (the 5 to 6-membered aromatic heterocyclyl group issubstituted with a C₁₋₃ alkyl group)).

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(XVI^(a)):

(wherein R^(12a) is a hydrogen atom), and R^(2a) is a C₁₋₃ alkyl group(the C₁₋₃ alkyl group is substituted with a phenyl group or a 5 to6-membered aromatic heterocyclyl group (the phenyl group and the 5 to6-membered aromatic heterocyclyl group are substituted with a C₁₋₃ alkylgroup or a C₁₋₃ haloalkyl group)) or a C₂₋₆ alkynyl group.

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(XVI^(a)):

(wherein R^(12a) is a hydrogen atom), and R^(2a) is a C₁₋₃ alkyl group(the C₁₋₃ alkyl group is substituted with a phenyl group or a 5 to6-membered aromatic heterocyclyl group (the phenyl group and the 5 to6-membered aromatic heterocyclyl group are substituted with a C₁₋₃ alkylgroup or a C₁₋₃ haloalkyl group and with a halogen atom)).

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(X^(a)-11):

(wherein R^(12a) is a C₁₋₃ alkyl group (the C₁₋₃ alkyl group issubstituted with a cyano group or a 5 to 6-membered aromaticheterocyclyl group (the 5 to 6-membered aromatic heterocyclyl group isunsubstituted or substituted with a C₁₋₃ alkyl group)) or a C₃₋₆cycloalkyl group), and R^(2a) is a C₁₋₃ alkyl group (the C₁₋₃ alkylgroup is unsubstituted or substituted with a cyano group) or a C₁₋₃haloalkyl group.

Another particularly preferred embodiment of the substituent L^(3a) andthe substituent R^(2a) is such that L^(3a) is represented by the formula(XVI^(a)):

(wherein R^(12a) is a C₁₋₃ alkyl group (the C₁₋₃ alkyl group issubstituted with a substituent selected from the group consisting of acyano group, a hydroxy group, a C₁₋₃ alkoxy group, a C₃₋₆ cycloalkylgroup and a phenyl group), a C₃₋₆ cycloalkyl group or a phenyl group),and R^(2a) is a C₁₋₃ alkyl group (the C₁₋₃ alkyl group is substitutedwith a substituent selected from the group consisting of a cyano group,a hydroxy group, a C₁₋₃ alkoxy group, a C₃₋₆ cycloalkyl group and aphenyl group).

A preferred embodiment of n^(a) and the substituent R^(3a) is such thatn^(a) is 0, 1 or 2, and R^(3a) is a hydroxy group, an amino group, ahalogen atom, a cyano group, a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group,a C₁₋₃ alkoxy group or a C₁₋₃ haloalkoxy group (when n^(a) is 2, R^(3a)'s may be identical or different).

Another preferred embodiment of n^(a) and the substituent R^(3a) is suchthat n^(a) is 0, 1 or 2, and R^(3a) is a carbamoyl group, a carboxygroup, a C₁₋₃ haloalkylcarbonyl group, a C₁₋₆ alkoxycarbonyl group, amono-C₁₋₃ alkylamino group, di-C₁₋₃ alkylamino group, mono-C₁₋₃alkylaminocarbonyl group, a di-C₁₋₃ alkylaminocarbonyl group or a C₁₋₃alkylcarbonylamino group (when n^(a) is 2, R^(3a) 's may be identical ordifferent).

A more preferred embodiment of n^(a) and the substituent R^(3a) is suchthat n^(a) is 0 or 1, and R^(3a) is a C₁₋₃ alkyl group.

Another more preferred embodiment of n^(a) and the substituent R^(3a) issuch that n^(a) is 0 or 1, and R^(3a) is a halogen atom.

Another more preferred embodiment of n^(a) and the substituent R^(1a) issuch that n^(a) is 0 or 1, and R^(3a) is a cyano group.

Another more preferred embodiment of n^(a) and the substituent R^(3a) issuch that n^(a) is 0 or 1, and R^(3a) is a hydroxy group.

Another more preferred embodiment of n^(a) and the substituent R^(3a) issuch that n^(a) is 2, and R^(3a) is a halogen atom or a C₁₋₃ alkyl group(R^(3a) 's may be identical or different).

As favorable tricyclic pyrimidine compounds of the present invention foruse as JAK inhibitors and as preventive, therapeutic and/or improvingagent for diseases against which inhibition of JAK is effective, thefollowing compounds may be mentioned.

1^(a)) Compounds represented by the formula (I^(a)):

[wherein R^(1a) is a hydrogen atom or a halogen atom,X^(a) is CR^(9a) (wherein R^(9a) is a hydrogen atom, a halogen atom, acyano group, a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group or a C₃₋₆cycloalkyl group) or a nitrogen atom,Y^(a) is CR^(10a) (wherein R^(10a) is a hydrogen atom), the ring A^(a)is represented by the following formula (II^(a)-1) or (II^(a)-2):

(wherein T^(1a) is a nitrogen atom or CR^(4a), U^(1a) is a nitrogen atomor CR^(5a), T^(2a) is a single bond, and E^(2a) is an oxygen atom or asulfur atom),the ring B^(a) is a C₃₋₁₁ cycloalkane, a C₃₋₁₁ cycloalkene (aring-constituting methylene group of the C₃₋₁₁ cycloalkane and the C₃₋₁₁cycloalkene may be replaced by a carbonyl group), a 3 to 11-memberednon-aromatic heterocycle, a C₆₋₁₄ aromatic carbocycle or a 5 to10-membered aromatic heterocycle,L^(1a) is a single bond or a C₁₋₆ alkylene group,L^(2a) is a single bond, a C₁₋₆ alkylene group, a C₂₋₆ alkenylene group(the C₁₋₆ alkylene group and the C₂₋₆ alkenylene group are unsubstitutedor substituted with one or more identical or different substituentsindependently selected from the group consisting of halogen atoms,hydroxy groups, amino groups and cyano groups), ═C(R^(15a))— (whereinR^(15a) is a hydrogen atom or a cyano group, and the bond connecting thering B^(a) and L^(2a) is a double bond) or ═C(R^(15a))—CH₂— (whereinR^(15a) is a hydrogen atom or a cyano group, and the bond connecting thering B^(a) and L^(3a) is a double bond),L^(3a) is a single bond or represented by any of the following formulae(XIV^(a)-1) to (XIV^(a)-15) or (XIII^(a)):

(wherein E^(1a) is an oxygen atom or a sulfur atom),when L^(3a) is a single bond, R^(2a) is a hydrogen atom, a halogen atom,an azido group, a C₃₋₁₁ cycloalkyl group, a 3 to 11-memberednon-aromatic heterocyclyl group, a C₆₋₁₄ aryl group, a 5 to 10-memberedaromatic heterocyclyl group, a 8 to 11-membered partially saturatedaromatic cyclic group or a 8 to 11-membered aromatic ring-condensedalicyclic hydrocarbon group (the C₃₋₁₁ cycloalkyl group, the 3 to11-membered non-aromatic heterocyclyl group, the C₆₋₁₄ aryl group, the 5to 10-membered aromatic heterocyclyl group, the 8 to 11-memberedpartially saturated aromatic cyclic group and the 8 to 11-memberedaromatic ring-condensed alicyclic hydrocarbon group are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the group consisting of the substituent setV^(4a), the substituent set V^(9a) and C₁₋₆ alkyl groups (the C₁₋₆ alkylgroups are substituted with a C₁₋₆ alkoxycarbonylamino group (the C₁₋₆alkoxycarbonylamino group is unsubstituted or substituted with one ormore identical or different halogen atoms independently selected fromthe group consisting of fluorine atoms, chlorine atoms, bromine atomsand iodine atoms)),when L^(3a) is not a single bond, R^(2a) is a hydrogen atom, a C₁₋₆alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group (the C₁₋₆ alkylgroup, the C₂₋₆ alkenyl group and the C₂₋₆ alkynyl group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(6a) andthe substituent set V^(9a)), a C₃₋₁₁ cycloalkyl group, a 3 to11-membered non-aromatic heterocyclyl group, a C₆₋₁₄ aryl group, a 5 to10-membered aromatic heterocyclyl group, a 8 to 11-membered partiallysaturated aromatic cyclic group or a 8 to 11-membered aromaticring-condensed alicyclic hydrocarbon group (the C₃₋₁₁ cycloalkyl group,the 3 to 11-membered non-aromatic heterocyclyl group, the C₆₋₁₄ arylgroup, the 5 to 10-membered aromatic heterocyclyl group, the 8 to11-membered partially saturated aromatic cyclic group and the 8 to11-membered aromatic ring-condensed alicyclic hydrocarbon group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(4a) andthe substituent set V^(9a)),n^(a) is 0, 1 or 2,R^(3a) is a hydroxy group, an amino group, a carboxy group, a carbamoylgroup, a sulfamoyl group, a phosphono group, a phosphonooxy group, asulfo group, a sulfoxy group, a tetrazolyl group, a halogen atom, acyano group, a nitro group, a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group,a C₃₋₁₁ cycloalkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ haloalkenylgroup, a C₁₋₆ alkoxy group, a C₁₋₆ haloalkoxy group, a C₁₋₆ alkylthiogroup, a C₁₋₆ haloalkylthio group, a C₁₋₆ alkylcarbonyl group, a C₁₋₆haloalkylcarbonyl group, a C₁-6 alkylsulfonyl group, a C₁₋₆haloalkylsulfonyl group, a C₁₋₆ alkoxycarbonyl group, a mono-C₁₋₆alkylamino group, a di-C₁₋₆ alkylamino group, a mono-C₁₋₆alkylaminocarbonyl group, a di-C₁₋₆ alkylaminocarbonyl group or a C₁₋₆alkylcarbonylamino group (when n^(a) is 2, R^(3a)'s may be identical ordifferent), each of R^(4a) and R^(5a) is independently a hydrogen atom,a hydroxy group, an amino group, a carboxy group, a carbamoyl group, atetrazolyl group, a halogen atom, a cyano group, a C₁₋₆ alkyl group, aC₂₋₆ alkenyl group, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthio group, a C₁₋₆alkylcarbonyl group, a C₁₋₆ alkylsulfonyl group, a mono-C₁₋₆ alkylaminogroup, a di-C₁₋₆ alkylamino group (the C₁₋₆ alkyl group, the C₂₋₆alkenyl group, the C₁₋₆ alkoxy group, the C₁₋₆ alkylthio group, the C₁₋₆alkylcarbonyl group, the C₁₋₆ alkylsulfonyl group, the mono-C₁₋₆alkylamino group and the di-C₁₋₆ alkylamino group are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the substituent set V^(3a)), a C₁₋₆alkoxycarbonyl group, a C₃₋₁₁ cycloalkyl group, a 3 to 11-memberednon-aromatic heterocyclyl group, a C₆₋₁₄ aryl group or a 5 to10-membered aromatic heterocyclyl group (the C₃₋₁₁ cycloalkyl group, the3 to 11-membered non-aromatic heterocyclyl group, the C₆₋₁₄ aryl groupand the 5 to 10-membered aromatic heterocyclyl group are unsubstitutedor substituted with one or more identical or different substituentsindependently selected from the substituent set V^(1a)),R^(6a) is a hydrogen atom, a C₁₋₆ alkyl group (the C₁₋₆ alkyl group isunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(3a)), aC₃₋₆ cycloalkyl group, a 4 to 7-membered non-aromatic heterocyclylgroup, a phenyl group or a 5 to 6-membered aromatic heterocyclyl group(the C₃₋₆ cycloalkyl group, the 4 to 7-membered non-aromaticheterocyclyl group, the phenyl group and the 5 to 6-membered aromaticheterocyclyl group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(1a)),each of R^(12a) and R^(13a) is independently a hydrogen atom, a C₁₋₆alkyl group, a C₁₋₆ haloalkyl group (the C₁₋₆ alkyl group and the C₁₋₆haloalkyl group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(2a), the substituent set V^(8a) and the substituentset V^(9a)), a C₃₋₁₁ cycloalkyl group, a 3 to 11-membered non-aromaticheterocyclyl group, a C₆₋₁₄ aryl group, a 5 to 10-membered aromaticheterocyclyl group, a 8 to 14-membered partially saturated aromaticcyclic group or a 8 to 14-membered aromatic ring-condensed alicyclichydrocarbon group (the C₃₋₁₁ cycloalkyl group, the 3 to 11-memberednon-aromatic heterocyclyl group, C₆₋₁₄ aryl group, the 5 to 10-memberedaromatic heterocyclyl group, the 8 to 14-membered partially saturatedaromatic cyclic group and the 8 to 14-membered aromatic ring-condensedalicyclic hydrocarbon group are unsubstituted or substituted with one ormore identical or different substituents independently selected from thesubstituent set V^(1a) or the substituent set V^(9a))], tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.2^(a)) The compounds according to 1^(a)), wherein R^(1a) is a hydrogenatom or a halogen atom,X^(a) is CR^(9a) (wherein R^(9a) is a hydrogen atom, a halogen atom, acyano group, a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group or a C₃₋₆cycloalkyl group) or a nitrogen atom,Y^(a) is CR^(10a) (wherein R^(10a) is a hydrogen atom),the ring A^(a) is represented by the following formula (II^(a)-1) or(II^(a)-2):

(wherein T^(1a) is a nitrogen atom or CR^(4a), U^(1a) is a nitrogen atomor CR^(5a), T^(2a) is a single bond, E^(2a) is an oxygen atom or asulfur atom, and R^(6a) is a hydrogen atom, a C₁₋₆ alkyl group (the C₁₋₆alkyl group is unsubstituted or substituted with one or more identicalor different substituents independently selected from the substituentset V^(3a)), a C₃₋₆ cycloalkyl group, a 4 to 7-membered non-aromaticheterocyclyl group, a phenyl group or a 5 to 6-membered aromaticheterocyclyl group (the C₃₋₆ cycloalkyl group, the 4 to 7-memberednon-aromatic heterocyclyl group, the phenyl group and the 5 to6-membered aromatic heterocyclyl group are unsubstituted or substitutedwith one or more identical or different substituents independentlyselected from the substituent set V^(1a))),L^(3a) is a single bond or a C₁₋₃ alkylene group,L^(2a) is a single bond, a C₁₋₆ alkylene group or a C₁₋₆ haloalkylenegroup (the C₁₋₆ alkylene group and the C₁₋₆ haloalkylene group areunsubstituted or substituted with a hydroxy group or a cyano group),the ring B^(a) is a C₃₋₁₁ cycloalkane, a C₃₋₁₁ cycloalkene, a 3 to11-membered non-aromatic heterocycle, a C₆₋₁₄ aromatic carbocycle or a 5to 10-membered aromatic heterocycle,n^(a) is 0 or 1, R^(3a) is a hydroxy group, an amino group, a carboxygroup, a carbamoyl group, a tetrazolyl group, a halogen atom, a cyanogroup, a nitro group, a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group, a C₃₋₆cycloalkyl group, a C₁₋₃ alkoxy group, a C₁₋₃ haloalkoxy group or a C₁₋₃alkylsulfonyl group, andL^(3a) is a single bond, and R^(2a) is a hydrogen atom, a halogen atom,a C₃₋₆ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclylgroup, a phenyl group or a 5 to 6-membered aromatic heterocyclyl group(the C₃₋₆ cycloalkyl group, the 3 to 11-membered non-aromaticheterocyclyl group, the phenyl group and the 5 to 6-membered aromaticheterocyclyl group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(4a)), or L^(3a) is represented by any of thefollowing formulae (V^(a)-1) to (V^(a)-11):

(wherein E^(1a) is an oxygen atom, and each of R^(12a) and R^(13a) isindependently a hydrogen atom or a C₁₋₆ alkyl group), and R^(2a) is ahydrogen atom, a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is unsubstitutedor substituted with one or more identical or different substituentsindependently selected from the substituent set V^(5a)), a C₃₋₆cycloalkyl group, a 4 to 7-membered non-aromatic heterocyclyl group, aphenyl group or a 5 to 6-membered aromatic heterocyclyl group (the C₃₋₆cycloalkyl group, the 4 to 7-membered non-aromatic heterocyclyl group,the phenyl group and the 5 to 6-membered aromatic heterocyclyl group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(4a)),and

each of R^(4a) and R^(5a) is independently a hydrogen atom, an aminogroup, a carbamoyl group, a halogen atom, a cyano group, a C₁₋₆ alkylgroup, a C₁₋₆ haloalkyl group, a C₃₋₆ cycloalkyl group, a C₁₋₆ alkoxygroup, a C₁₋₆ haloalkoxy group, a C₁₋₆ alkylsulfonyl group, a 4 to7-membered non-aromatic heterocyclyl group, a phenyl group or a 5 to6-membered aromatic heterocyclyl group, tautomers or pharmaceuticallyacceptable salts of the compounds or solvates thereof.

3^(a)) The compounds according to 2^(a)), wherein R^(1a) is a hydrogenatom, tautomers or pharmaceutically acceptable salts of the compounds orsolvates thereof.4^(a)) The compounds according to 2^(a)) or 3^(a)), wherein Y^(a) isCR^(10a) (wherein R^(10a) is a hydrogen atom), tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.5^(a)) The compounds according to any one of 2^(a)) to 4^(a)), whereinX^(a) is a nitrogen atom or CR^(9a) (wherein R^(9a) is a hydrogen atom,a halogen atom or a cyano group), tautomers or pharmaceuticallyacceptable salts of the compounds or solvates thereof.6^(a)) The compounds according to any one of 2^(a)) to 5^(a)), whereinX^(a) is CR^(9a) (wherein R^(9a) is a hydrogen atom), tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.7^(a)) The compounds according to any one of 2^(a)) to 6^(a)), whereinthe ring A^(a) is represented by any of the following formulae(IV^(a)-1) to (IV^(a)-3):

(wherein E^(2a) is an oxygen atom or a sulfur atom, R^(4a) is a hydrogenatom, an amino group, a carbamoyl group, a halogen atom, a cyano group,a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group, a C₃₋₆ cycloalkyl group, aC₁₋₆ alkoxy group, a C₁₋₆ haloalkoxy group, a C₁₋₆ alkylsulfonyl group,a 4 to 7-membered non-aromatic heterocyclyl group, a phenyl group or a 5to 6-membered aromatic heterocyclyl group, and R^(ha) is a hydrogenatom, a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group, a C₃₋₆ cycloalkylgroup, a 4 to 7-membered non-aromatic heterocyclyl group, a phenyl groupor a 5 to 6-membered aromatic heterocyclyl group), tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.8^(a)) The compounds according to any one of 2^(a)) to 7^(a)), whereinthe ring A^(a) is represented by any of the following formulae(VIII^(a)-1) to

tautomers or pharmaceutically acceptable salts of the compounds orsolvates thereof.9^(a)) The compounds according to any one of 2^(a)) to 8^(a)), whereinL^(a) is a single bond, tautomers or pharmaceutically acceptable saltsof the compounds or solvates thereof.10^(a)) The compounds according to any one of 2^(a)) to 9^(a)), whereinL^(2a) is a single bond or a C₁₋₃ alkylene group (the C₁₋₃ alkylenegroup is unsubstituted or substituted with a cyano group) or a C₁₋₃haloalkylene group, tautomers or pharmaceutically acceptable salts ofthe compounds or solvates thereof.11^(a)) The compounds according to any one of 2^(a)) to 9^(a)), whereinL^(2a) is a single bond or a methylene group, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.12^(a)) The compounds according to any one of 2^(a)) to 11^(a)), whereinthe ring B^(a) is a C₄₋₇ cycloalkane, benzene or a 4 to 7-memberednon-aromatic heterocycle, tautomers or pharmaceutically acceptable saltsof the compounds or solvates thereof.13^(a)) The compounds according to any one of 2^(a)) to 11^(a)), whereinthe ring B^(a) is cyclohexane, benzene or piperidine, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.14^(a)) The compounds according to any one of 2^(a)) to 11^(a)), whereinthe ring B^(a) is spiro[2,5]octane or adamantane, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.15^(a)) The compounds according to any one of 2^(a)) to 11^(a)), whereinthe ring B^(a) is cyclohexane, tautomers or pharmaceutically acceptablesalts of the compounds or solvates thereof.16^(a)) The compounds according to any one of 2^(a)) to 15^(a)), whereinn^(a) is 0 or 1, and R^(3a) is a methyl group, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.17^(a)) The compounds according to any one of 2^(a)) to 15^(a)), whereinn^(a) is 0 or 1, and R^(3a) is a halogen atom, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.18^(a)) The compounds according to any one of 2^(a)) to 15^(a)), whereinn^(a) is 0 or 1, and R^(3a) is a cyano group, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.19^(a)) The compounds according to any one of 2^(a)) to 15^(a)), whereinn^(a) is 0 or 1, and R^(3a) is a hydroxy group, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.20^(a)) The compounds according to any one of 2^(a)) to 15^(a)), whereinn^(a) is 0, tautomers or pharmaceutically acceptable salts of thecompounds or solvates thereof.21^(a)) The compounds according to any one of 2^(a)) to 20^(a)), whereinL^(3a) is a single bond, and R^(2a) is a hydrogen atom, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.22^(a)) The compounds according to any one of 2^(a)) to 20^(a)), whereinL^(3a) is a single bond, and R^(2a) is a halogen atom, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.23^(a)) The compounds according to any one of 2^(a)) to 20^(a)), whereinL^(3a) is a single bond, and R^(2a) is a C₃₋₆ cycloalkyl group or a 3 to11-membered non-aromatic heterocyclyl group (the C₃₋₆ cycloalkyl groupand the 3 to 11-membered non-aromatic heterocyclyl group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the group consisting of hydroxygroups, cyano groups, halogen atoms, carboxy groups, carbamoyl groups,C₁₋₆ alkyl groups (the C₁₋₆ alkyl groups are unsubstituted orsubstituted with a hydroxy group or a cyano group), C₁₋₆ haloalkylgroups, C₁₋₆ haloalkoxy groups, di-C₁₋₆ alkylamino groups, C₁₋₆alkylsulfonyl groups, mono-C₁₋₆ alkylaminocarbonyl groups, C₁₋₆alkylcarbonylamino groups (the mono-C₁₋₆ alkylaminocarbonyl groups andthe C₁₋₆ alkylcarbonylamino groups are unsubstituted or substituted withone or more identical or different halogen atoms independently selectedfrom the group consisting of fluorine atoms, chlorine atoms, bromineatoms and iodine atoms), 4 to 7-membered non-aromatic heterocyclylgroups and phenyl groups (the phenyl groups are unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of halogen atoms andC₁₋₆ haloalkyl groups)), tautomers or pharmaceutically acceptable saltsof the compounds or solvates thereof.24^(a)) The compounds according to 23^(a)), wherein L^(3a) is a singlebond, and R^(2a) is a cyclohexyl group or a cyclopentyl group (thecyclohexyl group and the cyclopentyl group are unsubstituted orsubstituted with a C₁₋₃ alkyl group or a C₁₋₃ haloalkyl group),tautomers or pharmaceutically acceptable salts of the compounds orsolvates thereof.25^(a)) The compounds according to 23^(a)), wherein L^(3a) is a singlebond, and R^(2a) is an azetidinyl group, a pyrrolidinyl group, apiperidinyl group, a morpholinyl group, a 1,1-dioxothiomorpholino group,a thiazolidinyl group, a piperadinyl group, an oxopiperadinyl group or aindolinyl group (the azetidinyl group, the pyrrolidinyl group, thepiperidinyl group, the morpholinyl group, the 1,1-dioxothiomorpholinogroup, the thiazolidinyl group, the piperadinyl group, theoxopiperadinyl group and the indolinyl group are unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of hydroxy groups,cyano groups, halogen atoms, carboxy groups, carbamoyl groups, C₁₋₆alkyl groups (the C₁₋₆ alkyl groups are unsubstituted or substitutedwith a hydroxy group or a cyano group), C₁₋₆ haloalkyl groups, C₁₋₆haloalkoxy groups, di-C₁₋₆ alkylamino groups, C₁₋₆ alkylsulfonyl groups,mono-C₁₋₆ alkylaminocarbonyl groups, C₁₋₆ alkylcarbonylamino groups (themono-C₁₋₆ alkylaminocarbonyl groups and the C₁₋₆ alkylcarbonylaminogroups are unsubstituted or substituted with one or more identical ordifferent halogen atoms independently selected from the group consistingof fluorine atoms, chlorine atoms, bromine atoms and iodine atoms), 4 to7-membered non-aromatic heterocyclyl groups and phenyl groups (thephenyl groups are unsubstituted or substituted with one or two identicalor different substituents independently selected from the groupconsisting of halogen atoms and C₁₋₆ haloalkyl groups)), tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.26^(a)) The compounds according to any one of 2^(a)) to 20^(a)), whereinL^(3a) is a single bond, and R^(2a) is a phenyl group or a 5 to10-membered aromatic heterocyclyl group (the phenyl group and the 5 to10-membered aromatic heterocyclyl group are unsubstituted or substitutedwith one or more identical or different substituents independentlyselected from the group consisting of halogen atoms, cyano groups,carbamoyl groups, C₁₋₆ alkyl groups, C₁₋₆ alkoxy groups, di-C₁₋₃alkylamino groups (the C₁₋₆ alkyl groups, the C₁₋₆ alkoxy groups and thedi-C₁₋₃ alkylamino groups are unsubstituted or substituted with ahydroxy group or a cyano group), C₁₋₆ alkylthio groups, C₁₋₆alkylsulfonyl groups, C₁₋₆ haloalkyl groups, C₁₋₆ haloalkoxy groups,C₁₋₆ haloalkylthio groups, 4 to 7-membered non-aromatic heterocyclylgroups and 5 to 6-membered aromatic heterocyclyl groups), tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.27^(a)) The compounds according to any one of 2^(a)) to 20^(a)), whereinL^(3a) is a single bond, and R^(2a) is a phenyl group or a 5 to6-membered aromatic heterocyclyl group (the phenyl group and the 5 to6-membered aromatic heterocyclyl group are unsubstituted or substitutedwith one, two or three identical or different substituents independentlyselected from the group consisting of halogen atoms, hydroxy groups,cyano groups, C₁₋₆ alkyl groups, C₁₋₆ alkoxy groups, C₁₋₆ alkylthiogroups, mono-C₁₋₃ alkylamino groups, alkylamino groups, C₁₋₆alkylsulfonyl groups (the C₁₋₆ alkyl group, the C₁₋₆ alkoxy group, theC₁₋₆ alkylthio group, the mono-C₁₋₃ alkylamino group, the di-C₁₋₃alkylamino group and the C₁₋₆ alkylsulfonyl group are unsubstituted orsubstituted with a hydroxy group or a cyano group), C₁₋₆ haloalkylgroups, C₁₋₆ haloalkoxy groups, C₁₋₆ haloalkylthio groups and C₁₋₆haloalkylsulfonyl groups), tautomers or pharmaceutically acceptablesalts of the compounds or solvates thereof.28^(a)) The compounds according to 27^(a)), wherein L^(3a) is a singlebond, and R^(2a) is a phenyl group (the phenyl group is unsubstituted orsubstituted with one, two or three identical or different substituentsindependently selected from the group consisting of halogen atoms, cyanogroups, C₁₋₃ alkyl groups, C₁₋₃ alkoxy groups (the C₁₋₃ alkoxy group isunsubstituted or substituted with a hydroxy group or a cyano group),C₁₋₃ alkylthio groups, C₁ alkylsulfonyl groups, C₁₋₃ haloalkyl groups,C₁₋₃ haloalkoxy groups, C₁₋₃ haloalkylthio groups, di-C₁₋₃ alkylaminogroups (the di-C₁₋₃ alkylamino groups are unsubstituted or substitutedwith a cyano group), carbamoyl groups and 5 to 6-membered aromaticheterocyclyl groups), tautomers or pharmaceutically acceptable salts ofthe compounds or solvates thereof.29^(a)) The compounds according to 27^(a)), wherein L^(3a) is a singlebond, and R^(2a) is a furanyl group, a thienyl group, a pyrazolyl group,an isoxazolyl group, a thiazolyl group, a thiadiazolyl group, anindazolyl group, a quinoxalinyl group, an oxazolyl group, abenzothiazolyl group, a triazolyl group or a pyridinyl group (thefuranyl group, the thienyl group, the pyrazolyl group, the isoxazolylgroup, the thiazolyl group, the thiadiazolyl group, the indazolyl group,the quinoxalinyl group, the oxazolyl group, the benzothiazolyl group,the triazolyl group and the pyridinyl group are unsubstituted orsubstituted with identical or different one, two or three substituentsindependently selected from the group consisting of halogen atoms, cyanogroups, C₁₋₃ alkyl groups (the C₁₋₃ alkyl groups are unsubstituted orsubstituted with a hydroxy group), C₁₋₃ haloalkyl groups, hydroxygroups, C₁₋₃ alkoxy groups, 4 to 7-membered non-aromatic heterocyclylgroup and C₁₋₃ haloalkoxy groups), tautomers or pharmaceuticallyacceptable salts of the compounds or solvates thereof.30^(a)) The compounds according to any one of 2^(a)) to 20^(a)), whereinL^(3a) is represented by the following formula (XI^(a)-11 or (XI^(a)-2):

andR^(2a) is a methyl group (the methyl group is unsubstituted orsubstituted with a cyano groups or a phenyl group), tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.31^(a)) The compounds according to any one of 2^(a)) to 20^(a)), whereinL^(3a) is represented by the formula (X^(a)-1):

andR^(2a) is a hydrogen atom, a C₁₋₃ alkyl group (the C₁₋₃ alkyl group isunsubstituted or substituted with a cyano group), a C₁₋₃ haloalkylgroup, a 4 to 7-membered non-aromatic heterocyclyl group or a phenylgroup (the 4 to 7-membered non-aromatic heterocyclyl group and thephenyl group are unsubstituted or substituted with a substituentselected from the group consisting of a hydroxy group, a halogen atom, aC₁₋₃ alkyl group and a C₁₋₃ haloalkyl group), tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.32^(a)) The compounds according to any one of 2^(a)) to 20^(a)), whereinL^(3a) is represented by the formula (X^(a)-10):

(wherein E^(1a) is NR^(11a) (wherein R^(11a) is a hydroxy group)), andR^(2a) is a hydrogen atom, tautomers or pharmaceutically acceptablesalts of the compounds or solvates thereof.33^(a)) The compounds according to any one of 2^(a)) to 20^(a)), whereinL^(3a) is represented by the formula (X^(a)-2):

andR^(2a) is a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is unsubstituted orsubstituted with a phenyl group), tautomers or pharmaceuticallyacceptable salts of the compounds or solvates thereof.34^(a)) The compounds according to any one of 2^(a)) to 20^(a)), whereinL^(3a) is represented by the formula (X^(a)-3):

andR^(2a) is a hydrogen atom, tautomers or pharmaceutically acceptablesalts of the compounds or solvates thereof.35^(a)) The compounds according to any one of 2^(a)) to 20^(a)), whereinL^(3a) is represented by the formula (X^(a)-3):

andR^(2a) is a C₁₋₃ alkyl group, tautomers or pharmaceutically acceptablesalts of the compounds or solvates thereof.36^(a)) The compounds according to any one of 2^(a)) to 20^(a)), whereinL^(3a) is represented by the formula (X^(a)-4):

andR^(2a) is a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group, a C₃₋₆ cycloalkylgroup or a phenyl group (the phenyl group is unsubstituted orsubstituted with a halogen atom), tautomers or pharmaceuticallyacceptable salts of the compounds or solvates thereof.37^(a)) The compounds according to any one of 2^(a)) to 20^(a)), whereinL^(3a) is represented by the formula (X^(a)-7):

(wherein R^(12a) is a hydrogen atom), and R^(2a) is a hydrogen atom, aC₁₋₆ alkyl group, a 6 haloalkyl group (the C₁₋₆ alkyl group and the C₁₋₆haloalkyl group are unsubstituted or substituted with one or twoidentical or different substituents independently selected from thegroup consisting of hydroxy groups, cyano groups and phenyl groups (thephenyl groups are unsubstituted or substituted with a halogen atom or acyano group)), a C₃₋₆ cycloalkyl group, a phenyl group or a 5 to6-membered aromatic heterocyclyl group (the C₃₋₆ cycloalkyl group, thephenyl group and the 5 to 6-membered aromatic heterocyclyl group areunsubstituted or substituted with a substituent selected from the groupconsisting of a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group and a halogenatom), tautomers or pharmaceutically acceptable salts of the compoundsor solvates thereof.38^(a)) The compounds according to any one of 2^(a)) to 20^(a)), whereinL^(3a) is represented by the formula (XVI^(a))

(wherein R^(12a) is a hydrogen atom, a C₁₋₆ alkyl group or C₁₋₆haloalkyl group), and R^(2a) is a hydrogen atom, a C₁₋₆ alkyl group, aC₁₋₆ haloalkyl group (the C₁₋₆ alkyl group and the C₁₋₆ haloalkyl groupare unsubstituted or substituted with a substituent selected from thegroup consisting of a hydroxy group, a cyano group, a C₁₋₃ alkoxy group,mono-C₁₋₃ alkylaminocarbonyl group (the mono-C₁₋₃ alkylaminocarbonylgroup is unsubstituted or substituted with one or more identical ordifferent halogen atoms independently selected from the group consistingof fluorine atoms, chlorine atoms, bromine atoms and iodine atoms), aC₃₋₆ cycloalkyl group, a 4 to 7-membered non-aromatic heterocyclylgroup, a phenyl group and a 5 to 6-membered aromatic heterocyclyl group(the C₃₋₆ cycloalkyl group, the 4 to 7-membered non-aromaticheterocyclyl group, the phenyl group and the 5 to 6-membered aromaticheterocyclyl group are unsubstituted or substituted with one or twoidentical or different substituents independently selected from thegroup consisting of halogen atoms, cyano groups, hydroxy groups, C₁₋₃alkoxy groups, C₁₋₃ haloalkoxy groups, C₁₋₃ haloalkylsulfonyl groups,C₁₋₆ alkoxycarbonyl groups, 4 to 7-membered non-aromatic heterocyclylgroups and phenyl groups (the phenyl groups are unsubstituted orsubstituted with a halogen atom))), a C₃₋₆ cycloalkyl group, a 4 to7-membered non-aromatic heterocyclyl group, a phenyl group or a 5 to6-membered aromatic heterocyclyl group (the C₃₋₆ cycloalkyl group, the 4to 7-membered non-aromatic heterocyclyl group, the phenyl group and the5 to 6-membered aromatic heterocyclyl group are unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of hydroxy groups,halogen atoms, cyano groups, C₁₋₃ alkyl groups (the C₁₋₃ alkyl groupsare unsubstituted or substituted with a substituent selected from thegroup consisting of a hydroxy group, a cyano group and a C₁₋₃ alkoxygroup), C₁₋₃ haloalkyl groups, C₁₋₃ alkoxy groups, C₁₋₃ haloalkoxygroups, C₁₋₃ haloalkylsulfonyl groups, 4 to 7-membered non-aromaticheterocyclyl groups and phenyl groups (the phenyl groups areunsubstituted or substituted with a halogen atom)), tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.39^(a)) The compounds according to any one of 2^(a)) to 20^(a)), whereinL^(3a) is represented by the formula (XVI^(a)):

(wherein R^(12a) is a hydrogen atom or a C₁₋₃ alkyl group), and R^(2a)is a hydrogen atom, a C₁₋₆ alkyl group or a C₁₋₆ haloalkyl group (theC₁₋₆ alkyl group and the C₁₋₆ haloalkyl group are substituted with asubstituent selected from the group consisting of a hydroxy group and acyano group and with a substituent selected from the group consisting ofa phenyl group and a 5 to 6-membered aromatic heterocyclyl group (thephenyl group and the 5 to 6-membered aromatic heterocyclyl group areunsubstituted or substituted with one or two identical or differentsubstituents independently selected from the group consisting of halogenatoms, cyano groups, C₁₋₃ alkoxy groups and C₁₋₃ alkylthio groups)),tautomers or pharmaceutically acceptable salts of the compounds orsolvates thereof.40^(a)) The compounds according to any one of 2^(a)) to 20^(a)), whereinL^(3a) is represented by the formula (X^(a)-11):

(wherein R^(12a) is a hydrogen atom, a C₁₋₃ alkyl group or a C₁₋₃haloalkyl group), and R^(2a) is a C₁₋₆ alkyl group (the C₁₋₆ alkyl groupis unsubstituted or substituted with a cyano group) or a C₁₋₆ haloalkylgroup, tautomers or pharmaceutically acceptable salts of the compoundsor solvates thereof.41^(a)) The compounds according to any one of 2^(a)) to 20^(a)), whereinL^(3a) is represented by the formula (X^(a)-12):

(wherein R^(12a) is a hydrogen atom or a C₁₋₃ alkyl group), and R^(2a)is a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is unsubstituted orsubstituted with a cyano group), a C₁₋₆ haloalkyl group or a C₃₋₆cycloalkyl group, tautomers or pharmaceutically acceptable salts of thecompounds or solvates thereof.42^(a)) The compounds according to any one of 2^(a)) to 20^(a)), whereinL^(3a) is represented by the formula (X^(a)-13):

(wherein R^(12a) is a hydrogen atom), and R^(2a) is a C₁₋₆ alkyl group,tautomers or pharmaceutically acceptable salts of the compounds orsolvates thereof.43^(a)) The compounds according to 1^(a)), wherein R^(1a) is a hydrogenatom,X^(a) is CR^(9a) (wherein R^(9a) is a hydrogen atom),Y^(a) is CR^(10a) (wherein R^(10a) is a hydrogen atom),the ring A^(a) is represented by any of the following formulae(VIII^(a)-1) to (VIII^(a)-5):

L^(3a) is a single bond,the ring B^(a) is a C₄₋₇ cycloalkane, (a ring-constituting methylenegroup of the C₄₋₇ cycloalkane may be replaced by a carbonyl group) or a4 to 7-membered non-aromatic heterocycle,n^(a) is 0 or 1,R^(3a) is a hydroxy group, a cyano group, a halogen atom or a C₁₋₃ alkylgroup,L^(2a) is a single bond, a C₁₋₆ alkylene group (the C₁₋₆ alkylene groupis unsubstituted or substituted with one or two identical or differentsubstituents independently selected from the group consisting of hydroxygroups and cyano groups), a C₁₋₆ haloalkylene group, a C₂₋₆ alkenylenegroup (the C₁₋₆ haloalkylene group and the C₂₋₆ alkenylene group areunsubstituted or substituted with one or two cyano groups),═C(R^(15a))—(wherein R^(15a) is a hydrogen atom or a cyano group, andthe bond connecting the ring B^(a) and L^(3a) is a double bond) or═C(R^(15a))—CH₂— (wherein R^(15a) is a hydrogen atom or a cyano group,and the bond connecting the ring B^(a) and L^(2a) is a double bond),tautomers or pharmaceutically acceptable salts of the compounds orsolvates thereof.44^(a)) The compounds according to 43^(a)), wherein the ring B^(a) iscyclohexane or piperidine, tautomers or pharmaceutically acceptablesalts of the compounds or solvates thereof.45^(a)) The compounds according to 43^(a)), wherein L^(2a) is a singlebond, a C₁₋₃ alkylene, a C₂₋₃ alkenylene group (the C₁₋₃ alkylene groupand the C₂₋₃ alkenylene group are unsubstituted or substituted with oneor two cyano groups) or a C₁₋₃ haloalkylene group, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.46^(a)) The compounds according to 43^(a)), wherein n^(a) is 0,tautomers or pharmaceutically acceptable salts of the compounds orsolvates thereof.47^(a)) The compounds according to any one of 1^(a)) or 43^(a)) to46^(a)), wherein L^(3a) is a single bond,R^(2a) is a hydrogen atom, a halogen atom, an azido group, a 3 to11-membered non-aromatic heterocyclyl group, a phenyl group, a 5 to10-membered aromatic heterocyclyl group or a 8 to 11-membered partiallysaturated aromatic cyclic group (the 3 to 11-membered non-aromaticheterocyclyl group, the phenyl group, the 5 to 10-membered aromaticheterocyclyl group and the 8 to 11-membered partially saturated aromaticcyclic group are unsubstituted or substituted with one, two or threeidentical or different substituents independently selected from thegroup consisting of hydroxy groups, amino groups, halogen atoms, cyanogroups, nitro groups, carbamoyl groups, sulfamoyl groups, C₁₋₆ alkylgroups, C₁₋₆ haloalkyl groups, C₁₋₆ alkoxy groups, C₁₋₆ haloalkoxygroups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups, C₁₋₆alkylthio groups, C₁₋₆ haloalkylthio groups, C₁₋₆ alkylcarbonyl groups,C₁₋₆ haloalkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆haloalkylsulfonyl groups, mono-C₁₋₆ alkylaminosulfonyl groups, di-C₁₋₆alkylaminosulfonyl groups, C₁₋₆ alkoxycarbonyl groups, mono-C₁₋₆alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups, C₁₋₆alkylcarbonylamino groups, C₁₋₆ alkoxycarbonylamino groups (the C₁₋₆alkoxycarbonyl groups, the mono-C₁₋₆ alkylaminocarbonyl groups, thedi-C₁₋₆ alkylaminocarbonyl groups, the C₁₋₆ alkylcarbonylamino groupsand the C₁₋₆ alkoxycarbonylamino groups are unsubstituted or substitutedwith one or more identical or different halogen atoms independentlyselected from the group consisting of fluorine atoms, chlorine atoms,bromine atoms and iodine atoms), C₃₋₆ cycloalkyl groups, 4 to 7-memberednon-aromatic heterocyclyl groups, phenyl groups and 5 to 6-memberedaromatic heterocyclyl groups), tautomers or pharmaceutically acceptablesalts of the compounds or solvates thereof.48^(a)) The compounds according to any one of 1^(a)) or 43^(a)) to46^(a)), wherein R^(2a) is a 3 to 11-membered non-aromatic heterocyclylgroup (the 3 to 11-membered non-aromatic heterocyclyl group isunsubstituted or substituted with one or two identical or differentsubstituents independently selected from the group consisting of cyanogroups, halogen atoms, hydroxy groups, amino groups, carbamoyl groups,sulfamoyl groups, C₁₋₃ alkyl groups (the C₁₋₃ alkyl groups areunsubstituted or substituted with a substituent selected from the groupconsisting of a cyano group, a hydroxy group and a C₁₋₆alkoxycarbonylamino group), C₁₋₃ haloalkyl groups, C₁₋₃ alkoxy groups,mono-C₁₋₃ alkylamino groups, di-C₁₋₃ alkylamino groups, C₁₋₃alkylsulfonyl groups, mono-C₁₋₃ alkylaminocarbonyl groups, di-C₁₋₃alkylaminocarbonyl groups, mono-C₁₋₃ alkylaminosulfonyl groups, di-C₁₋₃alkylaminosulfonyl groups, C₁₋₃ alkylcarbonylamino groups and C₁₋₆alkoxycarbonylamino groups (the C₁₋₃ alkoxy groups, the mono-C₁₋₃alkylamino groups, the di-C₁₋₃ alkylamino groups, the C₁₋₃ alkylsulfonylgroups, the mono-C₁₋₃ alkylaminocarbonyl groups, the di-C₁₋₃alkylaminocarbonyl groups, the mono-C₁₋₃ alkylaminosulfonyl groups, thedi-C₁₋₃ alkylaminosulfonyl groups, the C₁₋₃ alkylcarbonylamino groupsand the C₁₋₆ alkoxycarbonylamino groups are unsubstituted or substitutedwith one or more identical or different halogen atoms independentlyselected from the group consisting of fluorine atoms, chlorine atoms,bromine atoms and iodine atoms or with a cyano group)), tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.49^(a)) The compounds according to any one of 1^(a)) or 43^(a)) to46^(a)), wherein L^(3a) is represented by the formulae (XVI^(a)):

(wherein R^(12a) is a hydrogen atom, a C₁₋₃ alkyl group (the C₁₋₃ alkylgroup is unsubstituted or substituted with a substituent selected fromthe group consisting of a hydroxy group, a cyano group, a C₁₋₃ alkoxygroup, a C₃₋₆ cycloalkyl group and a phenyl group), a C₁₋₃ haloalkylgroup, a C₃₋₆ cycloalkyl group or a phenyl group (the phenyl group isunsubstituted or substituted with a halogen atom or a cyano group)), and

R^(2a) is a hydrogen atom, a C₁₋₆ alkyl group (the C₁₋₆ alkyl group isunsubstituted or substituted with a substituent selected from the groupconsisting of a hydroxy group, a cyano group, a C₁₋₃ alkoxy group, amono-C₁₋₃ alkylaminocarbonyl group (the C₁₋₃ alkoxy group and themono-C₁₋₃ alkylaminocarbonyl group are unsubstituted or substituted withone or more identical or different halogen atoms independently selectedfrom the group consisting of fluorine atoms, chlorine atoms, bromineatoms and iodine atoms), a C₃₋₆ cycloalkyl group, a 3 to 11-memberednon-aromatic heterocyclyl group, a phenyl group and a 5 to 10-memberedaromatic heterocyclyl group (the C₃₋₆ cycloalkyl group, the 3 to11-membered non-aromatic heterocyclyl group, the phenyl group and the 5to 10-membered aromatic heterocyclyl group are unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of halogen atoms, cyanogroups, C₁₋₃ alkyl groups, C₁₋₃ haloalkyl groups, C₁₋₃ alkoxy groups,C₁₋₃ haloalkoxy groups, C₁₋₃ alkylthio groups, C₁₋₃ haloalkylthiogroups, C₁₋₃ haloalkylsulfonyl groups and 4 to 7-membered non-aromaticheterocyclyl groups)), a C₁₋₆ haloalkyl group, a C₂₋₆ alkynyl group, aC₃₋₆ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclylgroup, a phenyl group, a naphthyl group, a 5 to 10-membered aromaticheterocyclyl group, a 8 to 11-membered partially saturated aromaticcyclic group or a 8 to 11-membered aromatic ring-condensed alicyclichydrocarbon group (the C₃₋₆ cycloalkyl group, the 3 to 11-memberednon-aromatic heterocyclyl group, the phenyl group, the naphthyl group,the 5 to 10-membered aromatic heterocyclyl group, the 8 to 11-memberedpartially saturated aromatic cyclic group and the 8 to 11-memberedaromatic ring-condensed alicyclic hydrocarbon group are unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of hydroxy groups,halogen atoms, cyano groups, C₁₋₃ alkyl groups, C₁₋₃ haloalkyl groups,C₁₋₃ alkoxy groups, C₁₋₃ haloalkoxy groups, C₁₋₃ alkylthio groups, C₁₋₃haloalkylthio groups, C₁₋₃ haloalkylsulfonyl groups and 4 to 7-memberednon-aromatic heterocyclyl groups), tautomers or pharmaceuticallyacceptable salts of the compounds or solvates thereof.

50^(a)) The compounds according to any one of 1^(a)) or 43^(a)) to46^(a)), wherein L^(3a) is represented by any of the following formulae(XX^(a)-1) to (XX^(a)-3):

(wherein R^(12a) is a hydrogen atom, a C₁₋₃ alkyl group (the C₁₋₃ alkylgroup is unsubstituted or substituted with a cyano group) or a C₁₋₃haloalkyl group), and R^(2a) is a hydrogen atom, a C₁₋₃ alkyl group or aC₁₋₃ haloalkyl group (the C₁₋₃ alkyl group and the C₁₋₃ haloalkyl groupare substituted with a substituent selected from the group consisting ofa hydroxy group and a cyano group and with a substituent selected fromthe group consisting of a 3 to 11-membered non-aromatic heterocyclylgroup, a phenyl group and a 5 to 10-membered aromatic heterocyclyl group(the 3 to 11-membered non-aromatic heterocyclyl group, the phenyl groupand the 5 to 10-membered aromatic heterocyclyl group are unsubstitutedor substituted with one or two identical or different substituentsindependently selected from the group consisting of halogen atoms, cyanogroups, C₁₋₃ alkyl groups, C₁₋₃ haloalkyl groups, C₁₋₃ alkoxy groups andC₁₋₃ alkylthio groups)), tautomers or pharmaceutically acceptable saltsof the compounds or solvates thereof.51^(a)) The compounds according to any one of 1^(a)) or 43^(a)) to46^(a)), wherein L^(3a) is represented by any of the following formulae(XXVI^(a)-1) to (XXVI^(a)-5):

(wherein E^(1a) is an oxygen atom, R^(12a) is a C₁₋₆ alkyl group (theC₁₋₆ alkyl group is unsubstituted or substituted with a substituentselected from the group consisting of a cyano group, a hydroxy group, aC₁₋₃ alkoxy group, a C₃₋₆ cycloalkyl group and a phenyl group), a C₁₋₆haloalkyl group, a C₃₋₆ cycloalkyl group or a phenyl group (the phenylgroup is unsubstituted or substituted with a halogen atom or a cyanogroup)), and

R^(2a) is a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is unsubstituted orsubstituted with a substituent selected from the group consisting of acyano group, a hydroxy group, a C₁₋₃ alkoxy group, a C₃₋₆ cycloalkylgroup and a phenyl group), a C₁₋₆ haloalkyl group, a C₃₋₆ cycloalkylgroup or a phenyl group (the phenyl group is unsubstituted orsubstituted with a halogen atom)), tautomers or pharmaceuticallyacceptable salts of the compounds or solvates thereof.

52^(a)) The compounds according to any one of any one of 1^(a)) or43^(a)) to 46^(a)), wherein L^(3a) is represented by the formula(X^(a)-11):

(wherein R^(12a) is a hydrogen atom, a C₁₋₃ alkyl group (the C₁₋₃ alkylgroup is unsubstituted or substituted with a cyano group or a 5 to6-membered aromatic heterocyclyl group (the 5 to 6-membered aromaticheterocyclyl group is unsubstituted or substituted with a C₁₋₃ alkylgroup)), a C₁₋₃ haloalkyl group or a C₃₋₆ cycloalkyl group), and R^(2a)is a C₁₋₃ alkyl group (the C₁₋₃ alkyl group is unsubstituted orsubstituted with a cyano group) or a C₁₋₃ haloalkyl group, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.53^(a)) The compounds according to any one of 1^(a)) or 43^(a)) to46^(a)), wherein L^(3a) is represented by the formula (X^(a)-5):

andR^(2a) is a C₁₋₃ alkyl group, tautomers or pharmaceutically acceptablesalts of the compounds or solvates thereof.54^(a)) The compounds according to any one of 1^(a)) or 43^(a)) to46^(a)), wherein L^(3a) is represented by the formula (X^(a)-6):

andR^(2a) is a hydrogen atom, tautomers or pharmaceutically acceptablesalts of the compounds or solvates thereof.55^(a)) The compounds according to any one of 1^(a)) or 43^(a)) to46^(a)), wherein L^(3a) is represented by the formula (XVIII^(a)):

(wherein R^(12a) is a hydrogen atom), and R^(2a) is a C₁₋₆ alkyl group(the C₁₋₆ alkyl group is unsubstituted or substituted with a phenylgroup), tautomers or pharmaceutically acceptable salts of the compoundsor solvates thereof.56^(a)) The compounds according to any one of 1^(a)) or 43^(a)) to46^(a)), wherein L^(3a) is represented by the formula (X^(a)-8):

andR^(2a) is a C₁₋₃ alkyl group, tautomers or pharmaceutically acceptablesalts of the compounds or solvates thereof.57^(a)) The compounds according to any one of 1^(a)), 2^(a)) or 43^(a))to 56^(a)), which is represented by the following formula (XXII^(a)-1)or (XXII^(a)-2):

tautomers or pharmaceutically acceptable salts of the compounds orsolvates thereof.58^(a)) Compounds represented by the formula (XII^(a)):

wherein X^(a) is CR^(9a) (wherein R^(9a) is a hydrogen atom, a halogenatom or a cyano group), and the rings A^(a) and B^(1a) are any of thefollowing combinations shown in Table^(a) 1, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.

The symbols in Table^(a) 1 denote the following substituents.

TABLE^(a) 1 A ^(a) B^(1 a) A ^(a) B 1 ^(a) A ^(a) B ^(1 a) A ^(a) B^(1 a) A 1 B ¹ 1 A 1 B ¹ 3 A 1 B ¹ 5 A 1 B ¹ 7 A 2 B ¹ 1 A 2 B ¹ 3 A 2 B¹ 5 A 2 B ¹ 7 A 3 B ¹ 1 A 3 B ¹ 3 A 3 B ¹ 5 A 3 B ¹ 7 A 4 B ¹ 1 A 4 B ¹3 A 4 B ¹ 5 A 4 B ¹ 7 A 5 B ¹ 1 A 5 B ¹ 3 A 5 B ¹ 5 A 5 B ¹ 7 A 6 B ¹ 1A 6 B ¹ 3 A 6 B ¹ 5 A 6 B ¹ 7 A 7 B ¹ 1 A 7 B ¹ 3 A 7 B ¹ 5 A 7 B ¹ 7 A8 B ¹ 1 A 8 B ¹ 3 A 8 B ¹ 5 A 8 B ¹ 7 A 1 B ¹ 2 A 1 B ¹ 4 A 1 B ¹ 6 A 1B ¹ 8 A 2 B ¹ 2 A 2 B ¹ 4 A 2 B ¹ 6 A 2 B ¹ 8 A 3 B ¹ 2 A 3 B ¹ 4 A 3 B¹ 6 A 3 B ¹ 8 A 4 B ¹ 2 A 4 B ¹ 4 A 4 B ¹ 6 A 4 B ¹ 8 A 5 B ¹ 2 A 5 B ¹4 A 5 B ¹ 6 A 5 B ¹ 8 A 6 B ¹ 2 A 6 B ¹ 4 A 6 B ¹ 6 A 6 B ¹ 8 A 7 B ¹ 2A 7 B ¹ 4 A 7 B ¹ 6 A 7 B ¹ 8 A 8 B ¹ 2 A 8 B ¹ 4 A 8 B ¹ 6 A 8 B ¹ 859 ^(a)) Compounds represented by the formula (XII^(a)−1):

wherein X^(a) is CR^(9a) (wherein R^(9a) is a hydrogen atom, a halogenatom or a cyano group), and the rings A^(a) and B^(2a) are any of thefollowing combinations shown in Table^(a) 2, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.

The symbols in Table^(a) 2 denote the following substituents.

TABLE^(a) 2 A ^(a) B ^(2 a) A ^(a) B ^(2 a) A ^(a) B ^(2 a) A ^(a) B^(2 a) A 1 B ² 1 A 1 B ² 3 A 1 B ² 5 A 1 B ² 7 A 2 B ² 1 A 2 B ² 3 A 2 B² 5 A 2 B ² 7 A 3 B ² 1 A 3 B ² 3 A 3 B ² 5 A 3 B ² 7 A 4 B ² 1 A 4 B ²3 A 4 B ² 5 A 4 B ² 7 A 5 B ² 1 A 5 B ² 3 A 5 B ² 5 A 5 B ² 7 A 6 B ² 1A 6 B ² 3 A 6 B ² 5 A 6 B ² 7 A 7 B ² 1 A 7 B ² 3 A 7 B ² 5 A 7 B ² 7 A8 B ² 1 A 8 B ² 3 A 8 B ² 5 A 8 B ² 7 A 1 B ² 2 A 1 B ² 4 A 1 B ² 6 A 1B ² 8 A 2 B ² 2 A 2 B ² 4 A 2 B ² 6 A 2 B ² 8 A 3 B ² 2 A 3 B ² 4 A 3 B² 6 A 3 B ² 8 A 4 B ² 2 A 4 B ² 4 A 4 B ² 6 A 4 B ² 8 A 5 B ² 2 A 5 B ²4 A 5 B ² 6 A 5 B ² 8 A 6 B ² 2 A 6 B ² 4 A 6 B ² 6 A 6 B ² 8 A 7 B ² 2A 7 B ² 4 A 7 B ² 6 A 7 B ² 8 A 8 B ² 2 A 8 B ² 4 A 8 B ² 6 A 8 B ² 860 ^(a))Compounds represented by the formula (XII^(a)−2):

wherein X^(a) is CR^(9a) (wherein R^(9a) is a hydrogen atom, a halogenatom or a cyano group), and the rings A^(a) and B^(3a) are any of thefollowing combinations shown in Table^(a) 3, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.

The symbols in Table^(a) 3 denote the following substituents.

TABLE^(a) 3 A ^(a) B ^(3 a) A ^(a) B ^(3 a) A ^(a) B ^(3 a) A ^(a) B^(3 a) A 1 B ³ 1 A 1 B ³ 3 A 1 B ³ 5 A 1 B ³ 7 A 2 B ³ 1 A 2 B ³ 3 A 2 B³ 5 A 2 B ³ 7 A 3 B ³ 1 A 3 B ³ 3 A 3 B ³ 5 A 3 B ³ 7 A 4 B ³ 1 A 4 B ³3 A 4 B ³ 5 A 4 B ³ 7 A 5 B ³ 1 A 5 B ³ 3 A 5 B ³ 5 A 5 B ³ 7 A 6 B ³ 1A 6 B ³ 3 A 6 B ³ 5 A 6 B ³ 7 A 7 B ³ 1 A 7 B ³ 3 A 7 B ³ 5 A 7 B ³ 7 A8 B ³ 1 A 8 B ³ 3 A 8 B ³ 5 A 8 B ³ 7 A 1 B ³ 2 A 1 B ³ 4 A 1 B ³ 6 A 1B ³ 8 A 2 B ³ 2 A 2 B ³ 4 A 2 B ³ 6 A 2 B ³ 8 A 3 B ³ 2 A 3 B ³ 4 A 3 B³ 6 A 3 B ³ 8 A 4 B ³ 2 A 4 B ³ 4 A 4 B ³ 6 A 4 B ³ 8 A 5 B ³ 2 A 5 B ³4 A 5 B ³ 6 A 5 B ³ 8 A 6 B ³ 2 A 6 B ³ 4 A 6 B ³ 6 A 6 B ³ 8 A 7 B ³ 2A 7 B ³ 4 A 7 B ³ 6 A 7 B ³ 8 A 8 B ³ 2 A 8 B ³ 4 A 8 B ³ 6 A 8 B ³ 861 ^(a)) Compounds represented by the formula (XII^(a)−3):

wherein X^(a) is CR^(9a) (wherein R^(9a) is a hydrogen atom, a halogenatom or a cyano group), the rings A^(a) and B^(4a) are any of thefollowing combinations shown in Table 4, tautomers or pharmaceuticallyacceptable salts of the compounds or solvates thereof.

The symbols in Table^(a) 4 denote the following substituents.

TABLE^(a) 4 A^(a) B^(4a) A^(a) B^(4a) A^(a) B^(4a) A^(a) B⁴ ^(a) A1 B⁴1A1 B⁴3 A1 B⁴5 A1 B⁴7 A2 B⁴1 A2 B⁴3 A2 B⁴5 A2 B⁴7 A3 B⁴1 A3 B⁴3 A3 B⁴5 A3B⁴7 A4 B⁴1 A4 B⁴3 A4 B⁴5 A4 B⁴7 A5 B⁴1 A5 B⁴3 A5 B⁴5 A5 B⁴7 A6 B⁴1 A6B⁴3 A6 B⁴5 A6 B⁴7 A7 B⁴1 A7 B⁴3 A7 B⁴5 A7 B⁴7 A8 B⁴1 A8 B⁴3 A8 B⁴5 A8B⁴7 A1 B⁴2 A1 B⁴4 A1 B⁴6 A1 B⁴8 A2 B⁴2 A2 B⁴4 A2 B⁴6 A2 B⁴8 A3 B⁴2 A3B⁴4 A3 B⁴6 A3 B⁴8 A4 B⁴2 A4 B⁴4 A4 B⁴6 A4 B⁴8 A5 B⁴2 A5 B⁴4 A5 B⁴6 A5B⁴8 A6 B⁴2 A6 B⁴4 A6 B⁴6 A6 B⁴8 A7 B⁴2 A7 B⁴4 A7 B⁴6 A7 B⁴8 A8 B⁴2 A8B⁴4 A8 B⁴6 A8 B⁴862 ^(a)) The compounds with the combinations of substituents as definedin any of 58 ^(a)) to 61 ^(a)), wherein X^(a) is converted to a nitrogenatom, tautomers or pharmaceutically acceptable salts of the compounds orsolvates thereof.

Next, the tricyclic pyridine compounds of the present inventionrepresented by the formula (I^(b)) will be described.

First, how the ring A^(b) is fused in the tricyclic pyridine compoundsof the present invention will be described.

As is indicated in the formula (I^(b)), the ring A^(b) is fused to thepyridine ring so as to have two carbon atoms in common and attached toL^(1b) via a nitrogen atom in the ring A^(b) in the formula (I^(b)).

Therefore, when the ring A^(b) is represented by the formula (II^(b)),

the molecule of the compounds as a whole is represented by the formula(I^(b))-2,

and when the ring A^(b) is represented by the formula (III^(b)),

the molecule as a whole is represented by the formula (I^(b))-3.

and when the ring A^(b) is represented by the formula (IV^(b)),

the molecule as a whole is represented by the formula (I^(b))-4.

In the present invention, the formulae representing L^(3b) indicate thatthe left ends of the formulae are bonded to L^(2b), and the right endsof the formulae are bonded to R^(2b).

In the present invention, L^(1b), L^(2b) and R^(3b) may be bounded tothe ring B^(b) in the formula (1 ^(b)) at any positions of the ringB^(a) without any particular restrictions.

Next, preferred structures of the respective substituents will bementioned.

A preferred embodiment of the substituent R^(1b) is a hydrogen atom or ahalogen atom.

A more preferred embodiment of the substituent R^(1b) is a hydrogenatom.

A preferred embodiment of the substituent X^(b) is a nitrogen atom orCR^(15b) (wherein R^(15b) is a hydrogen atom, a halogen atom, a cyanogroup, a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group or a C₃₋₆ cycloalkylgroup).

A more preferred embodiment of the substituent X^(b) is a nitrogen atomor CR^(15b) (wherein R^(15b) is a hydrogen atom).

Another more preferred embodiment of the substituent X^(b) is CR^(15b)(wherein R^(15b) is a halogen atom).

A further preferred embodiment of the substituent X^(b) is CR^(15b)(wherein R^(16b) is a hydrogen atom).

A preferred embodiment of the substituent Y^(b) is CR^(16b) (whereinR^(16b) is a hydrogen atom).

A preferred embodiment of the ring A^(b) is represented by the followingformula (IX^(b)-1) or (IX^(b)-2):

(wherein E^(2b) is an oxygen atom, a sulfur atom or NR^(17b), and eachof R^(6b) and R^(8b) is independently a hydrogen atom, an amino group, acarbamoyl group, a halogen atom, a cyano group, a C₁₋₆ alkyl group, aC₁₋₆ alkoxy group, a C₁₋₆ alkylsulfonyl group (the C₁₋₆ alkyl group, theC₁₋₆ alkoxy group and the C₁₋₆ alkylsulfonyl group are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the substituent set V^(3b)), a C₃₋₆cycloalkyl group, a 4 to 7-membered non-aromatic heterocyclyl group, aphenyl group or a 5 to 6-membered aromatic heterocyclyl group (the C₃₋₆cycloalkyl group, the 4 to 7-membered non-aromatic heterocyclyl group,the phenyl group and the 5 to 6-membered aromatic heterocyclyl group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(1b))).

Another preferred embodiment of the ring A^(b) is represented by any ofthe following formulae (X^(b)-1) to (X^(b)-10):

(wherein E^(2b) is an oxygen atom, a sulfur atom or NR^(17b), and eachof R^(4b), R^(5b), R^(6b), R^(8b) and R^(9b) is independently a hydrogenatom, an amino group, a carbamoyl group, a halogen atom, a cyano group,a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, a C₁₋₆ alkylcarbonyl group, aC₁₋₆ alkylsulfonyl group (the C₁₋₆ alkyl group, the C₁₋₆ alkoxy group,the C₁₋₆ alkylcarbonyl group and the C₁₋₆ alkylsulfonyl group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(3b)), aC₃₋₆ cycloalkyl group, a 4 to 7-membered non-aromatic heterocyclylgroup, a phenyl group or a 5 to 6-membered aromatic heterocyclyl group(the C₃₋₆ cycloalkyl group, the 4 to 7-membered non-aromaticheterocyclyl group, the phenyl group and the 5 to 6-membered aromaticheterocyclyl group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(1b)), and R^(10b) is a hydrogen atom, a C₁₋₆ alkylgroup (the C₁₋₆ alkyl group is unsubstituted or substituted with one ormore identical or different substituents independently selected fromsubstituent set V^(3b)), a C₃₋₆ cycloalkyl group, a 4 to 7-memberednon-aromatic heterocyclyl group, a phenyl group or a 5 to 6-memberedaromatic heterocyclyl group (the C₃₋₆ cycloalkyl group, the 4 to7-membered non-aromatic heterocyclyl group, the phenyl group and the 5to 6-membered aromatic heterocyclyl group are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the substituent set V^(1b))).

A more preferred embodiment of the ring A^(b) is represented by thefollowing formula (IX^(b)-1) or (IX^(b)-2):

(wherein E^(2b) is an oxygen atom, each of R^(6b) and R^(8b) isindependently a hydrogen atom, a halogen atom or a C₁₋₃ alkyl group).

Another more preferred embodiment of the ring A^(b) is represented byany of the following formulae (XXIII^(b)-1) to (XXIII^(b)-5):

(wherein E^(2b) is an oxygen atom, each of R^(4b), R^(5b), R^(8b) andR^(9b) is independently a hydrogen atom, a halogen atom or a C₁₋₃ alkylgroup, and R^(10b) is a hydrogen atom or a C₁₋₃ alkyl group).

Another more preferred embodiment of the ring A^(b) is represented bythe formula is represented by the formula (XXIV^(b)):

(wherein R^(10b) is a hydrogen atom or a C₁₋₃ alkyl group).

Another more preferred embodiment of the ring A^(b) is represented bythe formula is represented by the formula (XXIV^(b)):

(wherein R^(10b) is a C₁₋₆ alkyl group (the C₁₋₆ alkyl group isunsubstituted or substituted with one or two identical or differentsubstituents independently selected from the group consisting of cyanogroups, hydroxy groups, C₁₋₃ alkoxy groups, C₁₋₃ alkylthio groups,di-C₁₋₃ alkylamino groups, di-C₁₋₃ alkylaminocarbonyl groups, C₃₋₆cycloalkyl groups, 4 to 7-membered non-aromatic heterocyclyl groups,phenyl groups, and 5 to 6-membered aromatic heterocyclyl groups (thephenyl groups and the 5 to 6-membered aromatic heterocyclyl groups areunsubstituted or substituted with one or two identical or differentsubstituents independently selected from the group consisting of halogenatoms, C₁₋₃ alkyl groups and C₁₋₃ haloalkyl groups)), a C₁₋₆ haloalkylgroup, a C₃₋₆ cycloalkyl group or a 4 to 7-membered non-aromaticheterocyclyl group).

Another more preferred embodiment of the ring A^(b) is represented bythe formula is represented by the formula (XIV^(b)):

(wherein each of R^(4b) and R^(5b) is independently a hydrogen atom or aC₁₋₃ alkyl group, and R^(10b) is a C₁₋₆ alkyl group (the C₁₋₆ alkylgroup is unsubstituted or substituted with one or two identical ordifferent substituents independently selected from the group consistingof cyano groups, hydroxy groups, C₁₋₃ alkoxy groups, C₁₋₃ alkylthiogroups, alkylamino groups, di-C₁₋₃ alkylaminocarbonyl groups, C₃₋₆cycloalkyl groups, 4 to 7-membered non-aromatic heterocyclyl groups), aC₁₋₆ haloalkyl group, a C₃₋₆ cycloalkyl group or a 4 to 7-memberednon-aromatic heterocyclyl group).

A further preferred embodiment of the ring A^(b) is represented by theformula (XI^(b)):

(wherein each of R^(6b) and R^(8b) is independently a hydrogen atom, ahalogen atom or a C₁₋₃ alkyl group).

Another further preferred embodiment of the ring A^(b) is represented bythe formula (XII^(b)):

(wherein R^(8b) is a hydrogen atom, a halogen atom or a C₁₋₃ alkylgroup).

Another further preferred embodiment of the ring A^(b) is represented bythe formula (XIII^(b)):

(wherein R^(4b) is a hydrogen atom, a halogen atom or a C₁₋₃ alkylgroup).

Another further preferred embodiment of the ring A^(b) is represented bythe formula (XIV^(b)):

(wherein each of R^(4b), R^(5b) and R^(10b) is independently a hydrogenatom or a C₁₋₃ alkyl group).

Another further preferred embodiment of the ring A^(b) is represented bythe formula (XXIV^(b)):

(wherein R^(10b) is a hydrogen atom).

Another further preferred embodiment of the ring A^(b) is represented bythe formula (XXIV^(b)):

(wherein R^(10b) is a C₁₋₆ alkyl group (the C₁₋₆ alkyl group isunsubstituted or substituted with one or two identical or differentsubstituents independently selected from the group consisting of cyanogroups, hydroxy groups, C₁₋₃ alkoxy groups, C₁₋₃ alkylthio groups,di-C₁₋₃ alkylamino groups and 4 to 7-membered non-aromatic heterocyclylgroups), a C₁₋₆ haloalkyl group, a C₃₋₆ cycloalkyl group or a 4 to7-membered non-aromatic heterocyclyl group).

A particularly preferred embodiment of the A^(b) is represented by theformula (XI^(b)):

(wherein R^(6b) is a hydrogen atom, a halogen atom or a C₁₋₃ alkylgroup, and R^(8b) is a hydrogen atom).

Another particularly preferred embodiment of the A^(b) is represented bythe formula (XII^(b)):

(wherein R^(8b) is a hydrogen atom).

Another particularly preferred embodiment of the A^(b) is represented bythe formula (XIII^(b)):

(wherein R^(4b) is a hydrogen atom).

Another particularly preferred embodiment of the A^(b) is represented bythe formula (XIV^(b)):

(wherein each of R^(4b), R^(5b) and R^(10b) is a hydrogen atom).

A preferred embodiment of the substituent L^(1b) is a single bond or aC₁₋₃ alkylene group.

A more preferred embodiment of the substituent L^(1b) is a single bondor a methylene group.

A further preferred embodiment of the substituent L^(1b) is a singlebond.

A preferred embodiment of the ring B^(b) is a C₃₋₁₁ cycloalkane, a 3 to11-membered non-aromatic heterocycle, benzene or a 5 to 10-memberedaromatic heterocycle.

A more preferred embodiment of the B^(b) is a C₄₋₇ cycloalkane, a 4 to7-membered non-aromatic heterocycle or a 5 to 6-membered aromaticheterocycle.

Another more preferred embodiment of the B^(b) is adamantane.

A further preferred embodiment of the ring B^(b) is a C₄₋₇ cycloalkaneor a 4 to 7-membered non-aromatic heterocycle.

A particularly preferred embodiment of the ring B^(b) is cyclohexane orpiperidine.

A preferred embodiment of the substituent L^(2b) is a single bond, aC₁₋₃ alkylene group or a C₁₋₃ haloalkylene group (the C₁₋₃ alkylenegroup and the C₁₋₃ haloalkylene group are substituted with a cyanogroup).

Another preferred embodiment of the substituent L^(2b) is a C₁₋₃alkylene group, a C₁₋₃ haloalkylene group (the C₁₋₃ alkylene group andthe C₁₋₃ haloalkylene group are unsubstituted or substituted with ahydroxy group) or a C₂₋₆ alkenylene group (the C₂₋₆ alkenylene group isunsubstituted or substituted with a cyano group).

Another preferred embodiment of the substituent L^(2b) is a C₁₋₆alkylene group (the C₁₋₆ alkylene group is unsubstituted or substitutedwith one or two cyano groups) or a C₁₋₆ haloalkylene group.

A more preferred embodiment of the substituent L^(2b) is a single bondor a C₁₋₃ alkylene group.

Another more preferred embodiment of the substituent L^(2b) is a C₁₋₃alkylene group. (the C₁₋₃ alkylene group is substituted with a cyanogroup) or a C₁₋₃ haloalkylene group.

Another more preferred embodiment of the substituent L^(2b) is a C₂₋₃alkenylene group (the C₂₋₃ alkenylene group is substituted with a cyanogroup).

A further preferred embodiment of the substituent L^(2b) is a singlebond or a methylene group.

A preferred embodiment of the substituent L^(3b) and the substituentR^(2b) is such that L^(3b) is a single bond, and R^(2b) is a hydrogenatom, a halogen atom, a C₃₋₆ cycloalkyl group, a 3 to 11-memberednon-aromatic heterocyclyl group, a phenyl group or a 5 to 10-memberedaromatic heterocyclyl group (the C₃₋₆ cycloalkyl group, the 3 to11-membered non-aromatic heterocyclyl group, the phenyl group and the 5to 10-membered aromatic heterocyclyl group are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the substituent set V^(1b)).

Another preferred embodiment of the substituent L^(3b) and thesubstituent R^(2b) is such that L^(3b) is a single bond, and R^(2b) is ahydrogen atom, a halogen atom, a C₃₋₁₁ cycloalkyl group, a 3 to11-membered non-aromatic heterocyclyl group, a phenyl group, a naphthylgroup, a 5 to 10-membered aromatic heterocyclyl group or a 8 to11-membered partially saturated aromatic cyclic group (the C₃₋₁₁cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclyl group,the phenyl group, the naphthyl group, the 5 to 10-membered aromaticheterocyclyl group and the 8 to 11-membered partially saturated aromaticcyclic group are unsubstituted or substituted with one or more identicalor different substituents independently selected from the substituentset V^(4b) and the substituent set V^(9b)).

Another preferred embodiment of the substituent L^(3b) and thesubstituent R^(2b) is such that L^(3b) is represented by any of thefollowing formulae (VI^(b)-1) to (VI^(b)-11):

(wherein E^(1b) is an oxygen atom or a sulfur atom, and each of R^(12b)and R^(13b) is independently a hydrogen atom, a C₁₋₆ alkyl group or aC₁₋₆ haloalkyl group), and R^(2b) is a hydrogen atom, a C₁₋₆ alkyl group(the C₁₋₆ alkyl group is unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(5b)), a C₂₋₆ alkenyl group, a C₃₋₆ cycloalkyl group,a 3 to 11-membered non-aromatic heterocyclyl group, a phenyl group or a5 to 10-membered aromatic heterocyclyl group (the C₂₋₆ alkenyl group,the C₃₋₆ cycloalkyl group, the 3 to 11-membered non-aromaticheterocyclyl group, the phenyl group and the 5 to 10-membered aromaticheterocyclyl group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(4b)).

Another preferred embodiment of the substituent L^(3b) and thesubstituent R^(2b) is such that L^(3b) is represented by any of thefollowing formulae (VI^(b)-11 to (VI^(b)-111:

(wherein E^(1b) is an oxygen atom or a sulfur atom, and each of R^(12b)and R^(13b) is independently a hydrogen atom, a C₁₋₆ alkyl group or aC₁₋₆ haloalkyl group (the C₁₋₆ alkyl group and the C₁₋₆ haloalkyl groupare unsubstituted or substituted with one or two identical or differentsubstituents independently selected from the group consisting of cyanogroups, hydroxy groups, C₁₋₆ alkoxy groups, C₃₋₆ cycloalkyl groups, 4 to7-membered non-aromatic heterocyclyl groups, phenyl groups and 5 to6-membered aromatic heterocyclyl groups)), and R^(2b) is a hydrogenatom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group (the C₁₋₆ alkyl group andthe C₂₋₆ alkenyl group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(6b) and the substituent set V^(9b)), a C₃₋₆cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclyl group, aphenyl group, a 5 to 10-membered aromatic heterocyclyl group or a 8 to11-membered partially saturated aromatic cyclic group (the C₃₋₆cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclyl group,the phenyl group, the 5 to 10-membered aromatic heterocyclyl group andthe 8 to 11-membered partially saturated aromatic cyclic group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(4b) andthe substituent set V^(9b)).

A more preferred embodiment of the substituent L^(3b) and thesubstituent R^(2b) is such that L^(3b) is a single bond, and R^(2b) is ahydrogen atom, a halogen atom, a C₃₋₆ cycloalkyl group, a phenyl groupor a 5 to 6-membered aromatic heterocyclyl group (the C₃₋₆ cycloalkylgroup, the phenyl group and the 5 to 6-membered aromatic heterocyclylgroup are unsubstituted or substituted with one or more identical ordifferent substituents independently selected from the substituent setV^(1b)).

Another more preferred embodiment of the substituent L^(3b) and thesubstituent R^(2b) is such that L^(3b) is a single bond, and R^(2b) is ahydrogen atom, a halogen atom, a C₃₋₆ cycloalkyl group, a 4 to7-membered non-aromatic heterocyclyl group, a phenyl group or a 5 to10-membered aromatic heterocyclyl group (the C₃₋₆ cycloalkyl group, the4 to 7-membered non-aromatic heterocyclyl group, the phenyl group andthe 5 to 10-membered aromatic heterocyclyl group are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the substituent set V^(1b)).

Another more preferred embodiment of the substituent L^(3b) and thesubstituent R^(2b) is such that L^(3b) is a single bond, and R^(2b) is a4 to 7-membered non-aromatic heterocyclyl group, a phenyl group or a 5to 6-membered aromatic heterocyclyl group (the 4 to 7-memberednon-aromatic heterocyclyl group, the phenyl group and the 5 to6-membered aromatic heterocyclyl group are unsubstituted or substitutedwith one or two identical or different substituents independentlyselected from the group consisting of C₁₋₆ alkyl groups, C₁₋₆ alkoxygroups (the C₁₋₆ alkyl group and the C₁₋₆ alkoxy group are substitutedwith a hydroxy group or a cyano group), mono-C₁₋₆ alkylamino groups,di-C₁₋₆ alkylamino groups, the mono-C₁₋₆ alkylaminocarbonyl groups, thedi-C₁₋₆ alkylaminocarbonyl groups, C₁₋₆ alkylcarbonylamino groups (themono-C₁₋₆ alkylamino group, the di-C₁₋₆ alkylamino group, mono-C₁₋₆alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups and theC₁₋₆ alkylcarbonylamino groups are substituted with one or moreidentical or different halogen atoms independently selected from thegroup consisting of fluorine atoms, chlorine atoms, bromine atoms andiodine atoms), phenyl groups, 5 to 6-membered aromatic heterocyclylgroups (the phenyl group and the 5 to 6-membered aromatic heterocyclylgroup are unsubstituted or substituted with one or two identical ordifferent substituents independently selected from the group consistingof halogen atoms, cyano atoms and C₁₋₆ haloalkyl groups)).

Another more preferred embodiment of the substituent L^(3b) and thesubstituent R^(2b) is such that L^(3b) is a single bond, and R^(2b) is a8 to 11-membered partially saturated aromatic cyclic group (the 8 to11-membered partially saturated aromatic cyclic group is unsubstitutedor substituted with one or more identical or different substituentsindependently selected from the group consisting of hydroxy groups,amino groups, halogen atoms, cyano groups, nitro groups, carbamoylgroups, sulfamoyl groups, C₁₋₆ alkyl groups, C₁₋₆ haloalkyl groups, C₁₋₆alkoxy groups, C₁₋₆ haloalkoxy groups, mono-C₁₋₆ alkylamino groups,di-C₁₋₆ alkylamino groups, C₁₋₆ alkylthio groups, C₁₋₆ haloalkylthiogroups, C₁₋₆ alkylcarbonyl groups, C₁₋₆ haloalkylcarbonyl groups, C₁₋₆alkylsulfonyl groups, C₁₋₆ haloalkylsulfonyl groups and C₁₋₆alkoxycarbonyl groups).

Another more preferred embodiment of the substituent L^(3b) and thesubstituent R^(2b) is such that L^(3b) is represented by any of thefollowing formulae (XV^(b)-1) to (XV^(b)-9):

(wherein R^(12b) is a hydrogen atom or a C₁₋₆ alkyl group), and R^(2b)is a hydrogen atom, a C₁₋₆ alkyl group or a C₁₋₆ haloalkyl group (theC₁₋₆ alkyl group and the C₁₋₆ haloalkyl group are unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of hydroxy groups,amino groups, carbamoyl groups, sulfamoyl groups, tetrazolyl groups,cyano groups, nitro groups, C₃₋₆ cycloalkyl groups, C₁₋₃ alkoxy groups,C₁₋₆ haloalkoxy groups, C₁₋₃ alkylsulfonyl groups, C₁₋₃haloalkylsulfonyl groups, 4 to 7-membered non-aromatic heterocyclylgroups, phenyl groups and 5 to 6-membered aromatic heterocyclyl groups).

Another more preferred embodiment of the substituent L^(3b) and thesubstituent R^(2b) is such that L^(3b) is represented by any of thefollowing formulae (XV^(b)-1) to (XV^(b)-9):

(wherein R^(12b) is a hydrogen atom, a C₁₋₆ alkyl group or a C₁₋₆haloalkyl group), and R^(2b) is a C₁₋₆ alkyl group (the C₁₋₆ alkyl groupis substituted with a substituent selected from the group consisting ofa C₃₋₆ cycloalkyl group, a 4 to 7-membered non-aromatic heterocyclylgroup, a phenyl group and a 5 to 6-membered aromatic heterocyclyl group(the C₃₋₆ cycloalkyl group, the 4 to 7-membered non-aromaticheterocyclyl group, the phenyl group and the 5 to 6-membered aromaticheterocyclyl group is substituted with one or two identical or differentsubstituents independently selected from the group consisting of hydroxygroups, halogen atoms and cyano groups)), a C₃₋₆ cycloalkyl group, a 4to 7-membered non-aromatic heterocyclyl group, a phenyl group or a 5 to6-membered aromatic heterocyclyl group (the C₃₋₆ cycloalkyl group, the 4to 7-membered non-aromatic heterocyclyl group, the phenyl group and the5 to 6-membered aromatic heterocyclyl group are unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of hydroxy groups,halogen atoms, cyano groups, C₁₋₃ alkyl groups, C₁₋₃ haloalkyl groupsand C₁₋₆ alkoxycarbonyl groups).

Another more preferred embodiment of the substituent L^(3b) and thesubstituent R^(2b) is such that L^(3b) is represented by any of thefollowing formulae (XXXIV^(b)-1) to (XXXIV^(b)-3):

(wherein R^(12b) is a C₁₋₆ alkyl group (the C₁₋₆ alkyl group issubstituted with a substituent selected from the group consisting of acyano group, a hydroxy group and a phenyl group)), and R^(2b) is a C₁₋₆alkyl group (the C₁₋₆ alkyl group is unsubstituted or substituted with asubstituent selected from the group consisting of a hydroxy group, acyano group and a phenyl group) or a C₁₋₆ haloalkyl group.

A further preferred embodiment of the substituent L^(3b) and the R^(2b)is such that L^(3b) is a single bond, and R^(2b) is a hydrogen atom, aphenyl group (the phenyl group is unsubstituted or substituted with oneor more identical or different substituents independently selected fromthe group consisting of halogen atoms, hydroxy groups, cyano groups,C₁₋₃ alkyl groups, C₁₋₃ haloalkyl groups, C₁₋₃ alkoxy groups and C₁₋₃haloalkoxy groups).

Another further preferred embodiment of the substituent L^(3b) and theR^(2b) is such that L^(3b) is a single bond, and R^(2b) is a hydrogenatom, a C₃₋₆ cycloalkyl group, a phenyl group or a 5 to 6-memberedaromatic heterocyclyl group (the phenyl group and the 5 to 6-memberedaromatic heterocyclyl group are unsubstituted or substituted with one ormore identical or different substituents independently selected from thegroup consisting of halogen atoms, cyano groups, nitro groups, C₁₋₃alkyl groups, C₁₋₃ haloalkyl groups and C₁₋₃ alkoxycarbonyl groups).

Another further preferred embodiment of the substituent L^(3b) and theR^(2b) is such that L^(3b) is a single bond, and R^(2b) is an indolinylgroup.

Another further preferred embodiment of the substituent L^(3b) and theR^(2b) is such that L^(3b) is a single bond, and R^(2b) is a 4 to7-membered non-aromatic heterocyclyl group (the 4 to 7-memberednon-aromatic heterocyclyl group is unsubstituted or substituted with oneor more identical or different substituents independently selected fromthe group consisting of hydroxy groups, halogen atoms, cyano groups,C₁₋₆ alkyl groups, C₁₋₆ haloalkyl groups, C₁₋₆ alkoxy groups, C₁₋₆haloalkoxy groups and C₁₋₆ alkoxycarbonyl groups).

Another further preferred embodiment of the substituent L^(3b) and theR^(2b) is such that L^(3b) is a single bond, and R^(2b) is a 4 to7-membered non-aromatic heterocyclyl group (the 4 to 7-memberednon-aromatic heterocyclyl group is substituted with a C₁₋₆ alkyl groups(the C₁₋₆ alkyl group is substituted with a cyano group)).

Another further preferred embodiment of the substituent L^(3b) and theR^(2b) is such that L^(3b) is a single bond, and R^(2b) is a 8 to11-membered partially saturated aromatic cyclic group (the 8 to11-membered partially saturated aromatic cyclic group is unsubstitutedor substituted with one or more identical or different halogen atomsindependently selected from the group consisting of fluorine atoms,chlorine atoms, bromine atoms and iodine atoms).

Another further preferred embodiment of the substituent L^(3b) and theR^(2b) is such that L^(3b) is represented by the following formula(VIII^(b)-1) or (VIII^(b)-2):

andR^(2b) is a C₁₋₆ alkyl group or a C₁₋₃ haloalkyl group (the C₁₋₆ alkylgroup and the C₁₋₃ haloalkyl group are unsubstituted or substituted witha cyano group or a C₃₋₆ cycloalkyl group).

Another further preferred embodiment of the substituent L^(3b) and theR^(2b) is such that L^(3b) is represented by the following formula(VIII^(b)-1) or (VIII^(b)-2):

andR^(2b) is a C₁₋₃ alkyl group (the C₁₋₃ alkyl group is substituted with aphenyl group).

Another further preferred embodiment of the substituent L^(3b) and theR^(2b) is such that L^(3b) is represented by the following formula(VIII^(b)-1) or (VIII^(b)-2):

andR^(2b) is a C₁₋₃ alkyl group (the C₁₋₃ alkyl group is substituted with aphenyl group (the phenyl group is substituted with a halogen atom)), aC₃₋₆ cycloalkyl group, a phenyl group or a 5 to 6-membered aromaticheterocyclyl group (the C₃₋₆ cycloalkyl group, the phenyl group and the5 to 6-membered aromatic heterocyclyl group are unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of halogen atoms, cyanogroups, C₁₋₆ alkyl groups and C₁₋₃ haloalkyl groups).

Another further preferred embodiment of the substituent L^(3b) and theR^(2b) is such that L^(3b) is represented by the formula (XXV^(b)):

(wherein R^(12b) is a hydrogen atom), and R^(2b) is a phenyl group or a5 to 6-membered aromatic heterocyclyl group (the phenyl group and the 5to 6-membered aromatic heterocyclyl group are unsubstituted orsubstituted with a substituent selected from the group consisting of aC₁₋₃ alkyl group and a C₁₋₃ haloalkyl group).

Another further preferred embodiment of the substituent L^(3b) and theR^(2b) is such that L^(3b) is represented by the formula (XXVI^(b)):

andR^(2b) is a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is unsubstituted orsubstituted with a phenyl group).

Another further preferred embodiment of the substituent L^(3b) and theR^(2b) is such that L^(3b) is represented by the formula (XXVII^(b)):

andR^(2b) is a hydrogen atom or a C₁₋₃ alkyl group.

Another further preferred embodiment of the substituent L^(3b) and theR^(2b) is such that L^(3b) is represented by the formula (XXXV^(b)):

(wherein R^(12b) is a C₁₋₃ haloalkyl group), and R^(2b) is a C₁₋₆ alkylgroup (the C₁₋₆ alkyl group is unsubstituted or substituted with a cyanogroup) or a C₁₋₆ haloalkyl group.

Another further preferred embodiment of the substituent L^(3b) and theR^(2b) is such that L^(3b) is represented by the formula (XXXII^(b)):

(wherein R^(12b) is a hydrogen atom or a C₁₋₃ alkyl group), and R^(2b)is a hydrogen atom, a C₁₋₆ alkyl group or a C₁₋₆ haloalkyl group (theC₁₋₆ alkyl group and the C₁₋₆ haloalkyl group are unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of hydroxy groups,cyano groups, C₁₋₃ alkoxy groups, C₃₋₆ cycloalkyl groups, 4 to7-membered non-aromatic heterocyclyl groups, phenyl groups and 5 to6-membered aromatic heterocyclyl groups).

Another further preferred embodiment of the substituent L^(3b) and theR^(2b) is such that L^(3b) is represented by the formula (XXXII^(b)):

(wherein R^(12b) is a C₁₋₃ haloalkyl group), and R^(2b) is a hydrogenatom, a C₁₋₆ alkyl group or a C₁₋₆ haloalkyl group (the C₁₋₆ alkyl groupand the C₁₋₆ haloalkyl group are unsubstituted or substituted with oneor two identical or different substituents independently selected fromthe group consisting of hydroxy groups, cyano groups, C₁₋₃ alkoxygroups, C₃₋₆ cycloalkyl groups, 4 to 7-membered non-aromaticheterocyclyl groups, phenyl groups and 5 to 6-membered aromaticheterocyclyl groups).

Another further preferred embodiment of the substituent L^(3b) and theR^(2b) is such that L^(3b) is represented by the formula (XXXII^(b)):

(wherein R^(12b) is a hydrogen atom or a C₁₋₃ alkyl group), and R^(2b)is a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is substituted with a C₃₋₆cycloalkyl group (the C₃₋₆ cycloalkyl group is substituted with ahydroxy group)), a C₃₋₆ cycloalkyl group, a 4 to 7-membered non-aromaticheterocyclyl group, a phenyl group or a 5 to 6-membered aromaticheterocyclyl group (the C₃₋₆ cycloalkyl group, the 4 to 7-memberednon-aromatic heterocyclyl group, the phenyl group and the 5 to6-membered aromatic heterocyclyl group are unsubstituted or substitutedwith one or two identical or different substituents independentlyselected from the group consisting of C₁₋₃ alkyl groups, C₁₋₃ haloalkylgroups and C₁₋₆ alkoxycarbonyl groups).

Another further preferred embodiment of the substituent L^(3b) and theR^(2b) is such that L^(3b) is represented by the formula (XXXII^(b)):

(wherein R^(12b) is a C₁₋₃ alkyl group (the C₁₋₃ alkyl group issubstituted with a substituent selected from the group consisting of acyano group, a hydroxy group and a phenyl group)), and R^(2b) is a C₁₋₆alkyl group (the C₁₋₆ alkyl group is unsubstituted or substituted with asubstituent selected from the group consisting of a hydroxy group, acyano group and a phenyl group) or a C₁₋₆ haloalkyl group.

A particularly preferred embodiment of the substituent L^(3b) and theR^(2b) is such that L^(3b) is a single bond, and R^(2b) is a hydrogenatom or a phenyl group (the phenyl group is unsubstituted or substitutedwith one or more identical or different halogen atoms selected from thegroup consisting of fluorine atoms, chlorine atoms, bromine atoms andiodine atoms).

Another particularly preferred embodiment of the substituent L^(3b) andthe R^(2b) is such that L^(3b) is a single bond, and R^(2b) is a phenylgroup (the phenyl group is unsubstituted or substituted with one or twoidentical or different substituents independently selected from thegroup consisting of halogen atoms, cyano groups and C₁₋₃ haloalkylgroups).

Another particularly preferred embodiment of the substituent L^(3b) andthe R^(2b) is such that L^(3b) is a single bond, and R^(2b) is a 5 to6-membered aromatic heterocyclyl group (the 5 to 6-membered aromaticheterocyclyl group is unsubstituted or substituted with a substituentselected from the group consisting of a halogen atom, a cyano group, anitro group, a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group and a C₁₋₃alkoxycarbonyl group).

Another particularly preferred embodiment of the substituent L^(3b) andthe R^(2b) is such that L^(3b) is a single bond, and R^(2b) is a C₃₋₆cycloalkyl group.

Another particularly preferred embodiment of the substituent L^(3b) andthe R^(2b) is such that L^(3b) is a single bond, and R^(2b) is a 4 to7-membered non-aromatic heterocyclyl group (the 4 to 7-memberednon-aromatic heterocyclyl group is unsubstituted or substituted with oneor two identical or different substituents independently selected fromthe group consisting of hydroxy groups, halogen atoms, cyano groups,C₁₋₃ alkyl groups and C₁₋₃ haloalkyl groups).

Another particularly preferred embodiment of the substituent L^(3b) andthe R^(2b) is such that L^(3b) is represented by the following formula(VIII^(b)-1) or (VIII^(b)-2):

and R^(2b) is a methyl group (the methyl group is unsubstituted orsubstituted with a cyano group, a cyclopropyl group or a trifluoromethylgroup) or an isobutyl group.

Another particularly preferred embodiment of the substituent L^(3b) andthe R^(2b) is such that L^(3b) is represented by the following formula(VIII^(b)-1) or (VIII^(b)-2):

and R^(2b) is a phenyl group (the phenyl group is unsubstituted orsubstituted with a substituent selected from the group consisting of ahalogen atom, a cyano group and a C₁₋₃ haloalkyl group) or a 5 to6-membered aromatic heterocyclyl group (the 5 to 6-membered aromaticheterocyclyl group is unsubstituted or substituted with a halogen atom).

Another particularly preferred embodiment of the substituent L^(3b) andthe R^(2b) is such that L^(3b) is represented by the formula(XXXII^(b)):

(wherein R^(12b) is a hydrogen atom), and R^(2b) is a C₃₋₆ cycloalkylgroup or a 4 to 7-membered non-aromatic heterocyclyl group (the C₃₋₆cycloalkyl group and the 4 to 7-membered non-aromatic heterocyclyl groupare unsubstituted or substituted with one or two identical or differentsubstituents independently selected from the group consisting of C₁₋₃alkyl groups, C₁₋₃ haloalkyl groups and C₁₋₆ alkoxycarbonyl groups).

A preferred embodiment of n^(b) and the substituent R^(3b) is such thatn^(b) is 0, 1 or 2, and R^(3b) is a hydroxy group, an amino group, ahalogen atom, a cyano group, a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group,a C₁₋₃ alkoxy group or a C₁₋₃ haloalkoxy group (when n^(b) is 2,R^(3b)'s may be identical or different).

A more preferred embodiment of n^(b) and the substituent R^(3b) is suchthat n^(b) is 0 or 1, and R^(3b) is a C₁₋₃ alkyl group.

As favorable tricyclic pyridine compounds of the present invention foruse as JAK inhibitors and as preventive, therapeutic and/or improvingagent for diseases against which inhibition of JAK is effective, thefollowing compound may be mentioned.

1^(b)) Compounds represented by the formula (I^(b)):

[wherein R^(1b) is a hydrogen atom or a halogen atom,X^(b) is a nitrogen atom or CR^(15b) (wherein R^(15b) is a hydrogenatom, a halogen atom, a cyano group, a C₁₋₆ alkyl group, a C₁₋₆haloalkyl group or a C₃₋₆ cycloalkyl group),Y^(b) is CR^(16b) (wherein R^(16b) is a hydrogen atom),the ring A^(b) is represented by the formula (II^(b)):

(wherein T^(1b) is CR^(4b)R^(5b), C(═O), C(═S), C(═NR^(17b)), a sulfuratom, S(═O) or S(═O)₂, U^(1b) is a nitrogen atom or CR^(6b), and W^(1b)is a nitrogen atom or CR^(8b)), the formula (III^(b)):

(wherein T^(2b) is CR^(4b), U^(2b) is a nitrogen atom or CR^(6b), andW^(2b) is CR^(8b)R^(9b), C(═O), C(═S), C(═NR^(17b)), NR^(10b) an oxygenatom, a sulfur atom, S(═O) or S(═O)₂ (provided that when U^(2b) isCR^(6b), W^(2b) is not C(═O))) or the formula (IV^(b)):

(wherein T^(3b) is CR^(4b)R^(5b), C(═O), C(═S), C(═NR^(17b)), a sulfuratom, S(═O) or S(═O)₂, U^(3b) is CR^(6b)R^(7b), C(═O), C(═S),C(═NR^(17b)), NR^(19b), an oxygen atom, a sulfur atom, S(═O) or S(═O)₂,and W^(3b) is CR^(8b)R^(9b), C(═O), C(═S), C(═NR^(17b)), NR^(11b), anoxygen atom, a sulfur atom, S(═O) or S(═O)₂ (provided that when T^(3b)is CR^(4b)R^(5b), and U^(3b) is CR^(6b)R^(7b), W^(3b) is notCR^(8b)R^(9b))),L^(1b) is a single bond or a C₁₋₃ alkylene group,L^(2b) is a single bond, a C₁₋₆ alkylene group, a C₂₋₆ alkenylene groupor a C₂₋₆ alkynylene group (the C₁₋₆ alkylene group, the C₂₋₆ alkenylenegroup and the C₂₋₆ alkynylene group are unsubstituted or substitutedwith one or more identical or different substituents independentlyselected from the group consisting of halogen atoms, hydroxy groups,amino groups, cyano groups and nitro groups),the ring B^(b) is a C₃₋₁₁ cycloalkane, a C₃₋₁₁ cycloalkene, a 3 to11-membered non-aromatic heterocycle, a C₆₋₁₄ aromatic carbocycle or a 5to 10-membered aromatic heterocycle,n^(b) is 0 or 1,R^(3b) is a hydroxy group, an amino group, a carboxy group, a carbamoylgroup, a tetrazolyl group, a halogen atom, a cyano group, a nitro group,a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group, a C₃₋₆ cycloalkyl group, aC₁₋₃ alkoxy group, a C₁₋₃ haloalkoxy group or a C₁₋₃ alkylsulfonylgroup, andL^(3b) is a single bond or represented by any of the following formulae(XXII^(b)-1) to (XXII^(b)-15):

(wherein E^(1b) is an oxygen atom or a sulfur atom),when L^(3b) is a single bond, R^(2b) is a hydrogen atom, a halogen atom,a C₃₋₁₁ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclylgroup, a C₆₋₁₄ aryl group, a 5 to 10-membered aromatic heterocyclylgroup, a 8 to 11-membered partially saturated aromatic cyclic group or a8 to 11-membered aromatic ring-condensed alicyclic hydrocarbon group(the C₃₋₁₁ cycloalkyl group, the 3 to 11-membered non-aromaticheterocyclyl group, the C₆₋₁₄ aryl group, the 5 to 10-membered aromaticheterocyclyl group, the 8 to 11-membered partially saturated aromaticcyclic group and the 8 to 11-membered aromatic ring-condensed alicyclichydrocarbon group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(4b) and the substituent set V^(9b)),when L^(3b) is not a single bond, R^(2b) is a hydrogen atom, a C₁₋₆alkyl group, a C₂₋₆ alkenyl group (the C₁₋₆ alkyl group and the C₂₋₆alkenyl group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(6b) and the substituent set V^(9b)), a C₃₋₁₁cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclyl group, aC₆₋₁₄ aryl group, a 5 to 10-membered aromatic heterocyclyl group, a 8 to11-membered partially saturated aromatic cyclic group or a 8 to11-membered aromatic ring-condensed alicyclic hydrocarbon group (theC₃₋₁₁ cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclylgroup, the C₆₋₁₄ aryl group, the 5 to 10-membered aromatic heterocyclylgroup, the 8 to 11-membered partially saturated aromatic cyclic groupand the 8 to 11-membered aromatic ring-condensed alicyclic hydrocarbongroup are unsubstituted or substituted with one or more identical ordifferent substituents independently selected from the substituent setV^(4b) and the substituent set V^(9b)),n^(b) is 0, 1 or 2,R^(3b) is a hydroxy group, an amino group, a carboxy group, a carbamoylgroup, a sulfamoyl group, a phosphono group, a phosphonooxy group, asulfo group, a sulfoxy group, a tetrazolyl group, a halogen atom, acyano group, a nitro group, a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group,a C₃₋₁₁ cycloalkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ haloalkenylgroup, a C₁₋₆ alkoxy group, a C₁₋₆ haloalkoxy group, a C₁₋₆ alkylthiogroup, a C₁₋₆ haloalkylthio group, a C₁₋₆ alkylcarbonyl group, a C₁₋₆haloalkylcarbonyl group, a C₁-6 alkylsulfonyl group, a C₁₋₆haloalkylsulfonyl group, a C₁₋₆ alkoxycarbonyl group, a mono-C₁₋₆alkylamino group, a di-C₁₋₆ alkylamino group, a mono-C₁₋₆alkylaminocarbonyl group, a di-C₁₋₆ alkylaminocarbonyl group or a C₁₋₆alkylcarbonylamino group (when n^(b) is 2, R^(3b)'s may be identical ordifferent), each of R^(4b), R^(5b), R^(6b), R^(7b), R^(8b) and R^(9b) isindependently a hydrogen atom, a hydroxy group, an amino group, acarboxy group, a carbamoyl group, a tetrazolyl group, a halogen atom, acyano group, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxygroup, a C₁₋₆ alkylthio group, a C₁₋₆ alkylcarbonyl group, a C₁₋₆alkylsulfonyl group, a mono-C₁₋₆ alkylamino group, a di-C₁₋₆ alkylaminogroup (the C₁₋₆ alkyl group, the C₂₋₆ alkenyl group, the C₁₋₆ alkoxygroup, the C₁₋₆ alkylthio group, the C₁₋₆ alkylcarbonyl group, the C₁₋₆alkylsulfonyl group, the mono-C₁₋₆ alkylamino group and the di-C₁₋₆alkylamino group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(3b)), a C₁₋₆ alkoxycarbonyl group, a C₃₋₁₁ cycloalkylgroup, a 3 to 11-membered non-aromatic heterocyclyl group, a C₆₋₁₄ arylgroup or a 5 to 10-membered aromatic heterocyclyl group (the C₃₋₁₁cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclyl group,the C₆₋₁₄ aryl group and the 5 to 10-membered aromatic heterocyclylgroup are unsubstituted or substituted with one or more identical ordifferent substituents independently selected from the substituent setV^(1b)),each of R^(10b) and R^(11b) is independently a hydrogen atom, a C₁₋₆alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkylcarbonyl group, a C₁₋₆alkylsulfonyl group, a C₁₋₆ alkoxycarbonyl group, a mono-C₁₋₆alkylaminocarbonyl group, a di-C₁₋₆ alkylaminocarbonyl group (the C₁₋₆alkyl group, the C₂₋₆ alkenyl group, the C₁₋₆ alkylcarbonyl group, theC₁₋₆ alkylsulfonyl group, the C₁₋₆ alkoxycarbonyl group, the mono-C₁₋₆alkylaminocarbonyl group and the di-C₁₋₆ alkylaminocarbonyl group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(3b)), aC₃₋₁₁ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclylgroup, a C₆₋₁₄ aryl group or a 5 to 10-membered aromatic heterocyclylgroup (the C₃₋₁₁ cycloalkyl group, the 3 to 11-membered non-aromaticheterocyclyl group, the C₆₋₁₄ aryl group and the 5 to 10-memberedaromatic heterocyclyl group are unsubstituted or substituted with one ormore identical or different substituents independently selected from thesubstituent set V^(1b)), each of R^(12b) and R^(13b) is independently ahydrogen atom, a C₁₋₆ alkyl group or a C₁₋₆ haloalkyl group (the C₁₋₆alkyl group and the C₁₋₆ haloalkyl group are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the substituent set V^(3b), the substituentset V^(8b) and the substituent set V^(9b)), and R^(17b) is a hydrogenatom, a hydroxy group, a cyano group, a nitro group, a C₁₋₆ alkyl groupor a C₁₋₆ alkoxy group], tautomers or pharmaceutically acceptable saltsof the compounds or solvates thereof.2^(b)) The compounds according to 1^(b)), wherein R^(1b) is a hydrogenatom or a halogen atom,X^(b) is a nitrogen atom or CR^(15b) (wherein R^(15b) is a hydrogenatom, a halogen atom, a cyano group, a C₁₋₆ alkyl group, a C₁₋₆haloalkyl group or a C₃₋₆ cycloalkyl group),Y^(b) is CR^(16b) (wherein R^(18b) is a hydrogen atom),the ring A^(b) is represented by the formula (II^(b)):

(wherein T^(1b) is CR^(4b)R^(5b), C(═O), C(═S), C(═NR^(17b)), a sulfuratom, S(═O) or S(═O)₂, U^(1b) is a nitrogen atom or CR^(6b), and W^(1b)is a nitrogen atom or CR^(8b)), the formula (III^(b)):

(wherein T^(2b) is CR^(4b), U^(2b) is a nitrogen atom or CR^(6b), andW^(2b) is CR^(8b)R^(9b), C(═O), C(═S), C(═NR^(17b)), NR^(10b,) an oxygenatom, a sulfur atom, S(═O) or S(═O)₂ (provided that when U^(2b) isCR^(6b), W^(2b) is not C(═O))) or the formula (IV^(b)):

(wherein T^(3b) is CR^(4b)R^(5b), C(═O), C(═S), C(═NR^(17b)), a sulfuratom, S(═O) or S(═O)₂, U^(3b) is CR^(6b)R^(7b), C(═O), C(═S),C(═NR^(17b)), NR^(10b), an oxygen atom, a sulfur atom, S(═O) or S(═O)₂,and W^(3b) is CR^(8b)R^(9b), C(═O), C(═S), C(═NR^(17b)), NR^(11b), anoxygen atom, a sulfur atom, S(═O) or S(═O)₂ (provided that when T^(3b)is CR^(4b)R^(5b), and U^(3b) is CR^(8b)R^(7b), W^(3b) is notCR^(8b)R^(9b))),L^(1b) is a single bond or a C₁₋₃ alkylene group,L^(2b) is a single bond, a C₁₋₆ alkylene group or a C₁₋₆ haloalkylenegroup (the C₁₋₆ alkylene group and the C₁₋₆ haloalkylene group areunsubstituted or substituted with one or more hydroxy groups or one ormore cyano groups),the ring B^(b) is a C₃₋₁₁ cycloalkane, a C₃₋₁₁ cycloalkene, a 3 to11-membered non-aromatic heterocycle, a C₆₋₁₄ aromatic carbocycle or a 5to 10-membered aromatic heterocycle,n^(b) is 0 or 1,R^(3b) is a hydroxy group, an amino group, a carboxy group, a carbamoylgroup, a tetrazolyl group, a halogen atom, a cyano group, a nitro group,a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group, a C₃₋₆ cycloalkyl group, aC₁₋₃ alkoxy group, a C₁₋₃ haloalkoxy group or a C₁₋₃ alkylsulfonylgroup,L^(3b) is a single bond, and R^(2b) is a hydrogen atom, a halogen atom,a C₃₋₆ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclylgroup, a phenyl group or a 5 to 6-membered aromatic heterocyclyl group(the C₃₋₆ cycloalkyl group, the 3 to 11-membered non-aromaticheterocyclyl group, the phenyl group and the 5 to 6-membered aromaticheterocyclyl group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(4b)), orL^(3b) is represented by any of the following formulae (VI^(b)-1) to(VI^(b)-11):

(wherein E^(1b) is an oxygen atom, and each of R^(12b) and R^(13b) isindependently a hydrogen atom or a C₁₋₆ alkyl group), and R^(2b) is ahydrogen atom, a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is unsubstitutedor substituted with one or more identical or different substituentsindependently selected from the substituent set V^(5b)), a C₃₋₆cycloalkyl group, a 4 to 7-membered non-aromatic heterocyclyl group, aphenyl group or a 5 to 6-membered aromatic heterocyclyl group (the C₃₋₆cycloalkyl group, the 4 to 7-membered non-aromatic heterocyclyl group,the phenyl group and the 5 to 6-membered aromatic heterocyclyl group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the substituent set V^(4b)),each of R^(4b), R^(5b), R^(6b), R^(7b), R^(8b) and R^(9b) isindependently a hydrogen atom, an amino group, a carbamoyl group, ahalogen atom, a cyano group, a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group,a C₁₋₆ alkoxy group, a C₁₋₆ haloalkoxy group, a C₁₋₆ alkylsulfonylgroup, a C₃₋₆ cycloalkyl group, a 4 to 7-membered non-aromaticheterocyclyl group, a phenyl group or a 5 to 6-membered aromaticheterocyclyl group (the phenyl group and the 5 to 6-membered aromaticheterocyclyl group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(1b)),each of R^(10b) and R^(11b) is independently a hydrogen atom, a C₁₋₆alkyl group, a C₁₋₆ haloalkyl group, a C₃₋₆ cycloalkyl group, a C₁₋₆alkoxy group, a C₁₋₆ haloalkoxy group, a C₁₋₆ alkylsulfonyl group, a 4to 7-membered non-aromatic heterocyclyl group, a phenyl group or a 5 to6-membered aromatic heterocyclyl group (the phenyl group and the 5 to6-membered aromatic heterocyclyl group are unsubstituted or substitutedwith one or more identical or different substituents independentlyselected from the substituent set V^(1b)), andR^(17b) is a hydrogen atom, a hydroxy group, a cyano group, a nitrogroup, a C₁₋₆ alkyl group or a C₁₋₆ alkoxy group, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.3^(b)) The compounds according to 1^(b)) or 2^(b)), wherein R^(1b) is ahydrogen atom, tautomers or pharmaceutically acceptable salts of thecompounds or solvates thereof.4^(b)) The compounds according to any one of 1^(b)) to 3^(b)), whereinX^(b) is a nitrogen atom or a CR^(15b) (wherein R^(15b) is a hydrogenatom, a halogen atom or a cyano group) or a nitrogen atom, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.5^(b)) The compounds according to any one of 1^(b)) to 4^(b)), whereinX^(b) is a nitrogen atom or CR^(15b) (wherein R^(15b) is a hydrogenatom), tautomers or pharmaceutically acceptable salts of the compoundsor solvates thereof.6^(b)) The compounds according to any one of 1^(b)) to 5^(b)), whereinY^(b) is CR^(16b) (wherein R^(16b) is a hydrogen atom), tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.7^(b)) The compounds according to any one of 1^(b)) to 6^(b)), whereinthe ring A^(b) is represented by any of the following formulae(VII^(b)-1) to (VII^(b)-7):

(wherein E^(2b) is an oxygen atom or a sulfur atom, each of each ofR^(4b), R^(5b), R^(6b), R^(8b) and R^(9b) is independently a hydrogenatom, an amino group, a carbamoyl group, a halogen atom, a cyano group,a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group, a C₃₋₆ cycloalkyl group, aC₁₋₆ alkoxy group, a C₁₋₆ haloalkoxy group, a C₁₋₆ alkylsulfonyl group,a 4 to 7-membered non-aromatic heterocyclyl group, a phenyl group or a 5to 6-membered aromatic heterocyclyl group, and R^(10b) is a hydrogenatom, a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group, a C₃₋₆ cycloalkylgroup, a C₁₋₆ alkoxy group, a C₁₋₆ haloalkoxy group, a C₁₋₆alkylsulfonyl group, a 4 to 7-membered non-aromatic heterocyclyl group,a phenyl group or a 5 to 6-membered aromatic heterocyclyl group),tautomers or pharmaceutically acceptable salts of the compounds orsolvates thereof.8^(b)) The compounds according to any one of 1^(b)) to 6^(b)), whereinthe ring A^(b) is represented by the formula (XXVIII^(b)):

(wherein each of E^(2b) and E^(3b) is independently, an oxygen atom or asulfur atom, and R^(10b) is a hydrogen atom, a C₁₋₆ alkyl group (theC₁₋₆ alkyl group is unsubstituted or substituted with one or twoidentical or different substituents independently selected from thegroup consisting of cyano groups, hydroxy groups, C₁₋₃ alkoxy groups,C₁₋₃ alkylthio groups, di-C₁₋₃ alkylamino groups, di-C₁₋₃alkylaminocarbonyl groups, C₃₋₆ cycloalkyl groups and 4 to 7-memberednon-aromatic heterocyclyl groups), a C₁₋₆ haloalkyl group, a C₃₋₆cycloalkyl group or a 4 to 7-membered non-aromatic heterocyclyl group),tautomers or pharmaceutically acceptable salts of the compounds orsolvates thereof.9^(b)) The compounds according to any one of 1^(b)) to 7^(b)), whereinthe ring A^(b) is represented by any of the following formulae(XVI^(b)-1) to (XVI^(b)-7):

(wherein R^(4b) is a hydrogen atom or a methyl group), tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.10^(b)) The compounds according to any one of 1^(b)) to 6^(b)), whereinthe ring A^(b) is represented by any of the following formula(XXIX^(b)-1) or (XXIX^(b)-2)

(wherein E^(2b) and E^(3b) are oxygen atoms, R^(6b) is a hydrogen atom,a halogen atom or a C₁₋₃ alkyl group, and R^(8b) and R^(10b) arehydrogen atoms), tautomers or pharmaceutically acceptable salts of thecompounds or solvates thereof.11^(b)) The compounds according to any one of 1^(b)) to 10^(b)), whereinL^(1b) is a single bond, tautomers or pharmaceutically acceptable saltsof the compounds or solvates thereof.12^(b)) The compounds according to any one of 1^(b)) to 11^(b)), whereinL^(2b) is a single bond or a C₁₋₆ alkylene group, a C₁₋₆ alkenylenegroup (the C₁₋₆ alkylene group and the C₁₋₆ alkenylene group areunsubstituted or substituted with a cyano group) or a C₁₋₆ haloalkylenegroup, tautomers or pharmaceutically acceptable salts of the compoundsor solvates thereof.13^(b)) The compounds according to any one of 1^(b)) to 11^(b)), whereinL^(2b) is a single bond or a C₁₋₃ alkylene group, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.14^(b)) The compounds according to any one of 1^(b)) to 11^(b)), whereinL^(2b) is a single bond or a methylene group, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.15^(b)) The compounds according to any one of 1^(b)) to 14^(b)), whereinthe ring B^(b) is a C₄₋₇ cycloalkane or a 4 to 7-membered non-aromaticheterocycle, tautomers or pharmaceutically acceptable salts of thecompounds or solvates thereof.16^(b)) The compounds according to any one of 1^(b)) to 14^(b)), whereinthe ring B^(b) is cyclohexane or piperidine, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.17^(b)) The compounds according to any one of 1^(b)) to 16^(b)), whereinn^(b) is, 0 or 1, and R^(3b) is a methyl group, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.18^(b)) The compounds according to any one of 1^(b)) to 17^(b)), whereinL^(3b) is a single bond, and R^(2b) is a hydrogen atom, a C₃₋₆cycloalkyl group, a 4 to 7-membered non-aromatic heterocyclyl group, aphenyl group or a 5 to 10-membered aromatic heterocyclyl group (theC₃₋₁₁ cycloalkyl group, the 4 to 7-membered non-aromatic heterocyclylgroup, the phenyl group and the 5 to 10-membered aromatic heterocyclylgroup are unsubstituted or substituted with one or more identical ordifferent substituents independently selected from the substituent setV^(1b)), tautomers or pharmaceutically acceptable salts of the compoundsor solvates thereof.19^(b)) The compounds according to any one of 1^(b)) to 17^(b)), whereinL^(3b) is a single bond, and R^(2b) is a hydrogen atom, a 4 to7-membered non-aromatic heterocyclyl group, a phenyl group or a 5 to6-membered aromatic heterocyclyl group (the 4 to 7-membered non-aromaticheterocyclyl group, the phenyl group and the 5 to 6-membered aromaticheterocyclyl group are unsubstituted or substituted with one or twoidentical or different substituents independently selected from thegroup consisting of hydroxy groups, halogen atoms, cyano groups, nitrogroups, C₁₋₆ alkyl groups, C₁₋₆ alkoxy groups and C₁₋₆ alkoxycarbonylgroups (the C₁₋₆ alkyl groups, the C₁₋₆ alkoxy groups and the C₁₋₆alkoxycarbonyl groups are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thegroup consisting of halogen atoms and cyano groups)), tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.20^(b)) The compounds according to any one of 1^(b)) to 17^(b)), whereinL^(3b) is a single bond, and R^(2b) is a hydrogen atom or a phenyl group(the phenyl group is unsubstituted or substituted with one or twohalogen atoms), tautomers or pharmaceutically acceptable salts of thecompounds or solvates thereof.21^(b)) The compounds according to any one of 1^(b)) to 17^(b)), whereinL^(3b) is a single bond, and R^(2b) is a C₃₋₆ cycloalkyl group,tautomers or pharmaceutically acceptable salts of the compounds orsolvates thereof.22^(b)) The compounds according to any one of 1^(b)) to 17^(b)), whereinL^(3b) is a single bond, and R^(2b) is a 4 to 7-membered non-aromaticheterocyclyl group (the 4 to 7-membered non-aromatic heterocyclyl groupis unsubstituted or substituted with one or more identical or differentsubstituents independently selected from the group consisting of hydroxygroups, halogen atoms, cyano groups, C₁₋₆ alkyl groups (the C₁₋₆ alkylgroups are unsubstituted or substituted with a cyano group), C₁₋₆haloalkyl groups, C₁₋₆ alkoxy groups, C₁₋₆ haloalkoxy groups and C₁₋₆alkoxycarbonyl groups), tautomers or pharmaceutically acceptable saltsof the compounds or solvates thereof.23^(b)) The compounds according to any one of 1^(b)) to 17^(b)), whereinL^(3b) is represented by any of the following formulae (XIX^(b)-1) to(XIX^(b)-7):

(wherein E^(1b) is an oxygen atom, and R^(12b) is a hydrogen atom or aC₁₋₃ alkyl group), and R^(2b) is a hydrogen atom, a C₁₋₆ alkyl group, aC₁₋₆ haloalkyl group (the C₁₋₆ alkyl group and the C₁₋₆ haloalkyl groupare unsubstituted or substituted with a substituent selected from thegroup consisting of a cyano group, a hydroxy group, a C₃₋₆ cycloalkylgroup, a phenyl group and a 5 to 6-membered aromatic heterocyclyl group(the C₃₋₆ cycloalkyl group, the phenyl group and the 5 to 6-memberedaromatic heterocyclyl group are unsubstituted or substituted with one ortwo identical or different substituents independently selected from thegroup consisting of halogen atoms, cyano groups, C₁₋₃ alkoxy groups,C₁₋₃ haloalkoxy groups, C₁₋₃ alkylsulfonyl groups and C₁₋₃haloalkylsulfonyl groups)), a C₃₋₆ cycloalkyl group, a phenyl group or a5 to 6-membered aromatic heterocyclyl group (the C₃₋₆ cycloalkyl group,the phenyl group and the 5 to 6-membered aromatic heterocyclyl group areunsubstituted or substituted with one or two identical or differentsubstituents independently selected from the group consisting of halogenatoms, cyano groups, C₁₋₆ alkyl groups, C₁₋₃ haloalkyl groups, C₁₋₃alkoxy groups, C₁₋₃ haloalkoxy groups, C₁₋₃ alkylsulfonyl groups andC₁₋₃ haloalkylsulfonyl groups), tautomers or pharmaceutically acceptablesalts of the compounds or solvates thereof.24^(b)) The compounds according to any one of 1^(b)) to 17^(b)), whereinL^(3b) is represented by the following formula (VIII^(b)-1) or(VIII^(b)-2):

and R^(2b) is a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is unsubstitutedor substituted with a substituent selected from the group consisting ofa cyano group, a C₃₋₆ cycloalkyl group, a phenyl group and a 5 to6-membered aromatic heterocyclyl group (the phenyl group, the 5 to6-membered aromatic heterocyclyl group are unsubstituted or substitutedwith one or two identical or different substituents independentlyselected from the group consisting of halogen atoms and cyano groups))or a C₁₋₃ haloalkyl group, tautomers or pharmaceutically acceptablesalts of the compounds or solvates thereof.25^(b)) The compounds according to any one of 1^(b)) to 17^(b)), whereinL^(3b) is represented by the following formula (VIII^(b)-1) or(VIII^(b)-2):

and R^(2b) is a methyl group (the methyl group is unsubstituted orsubstituted with a cyano groups, a cyclopropyl groups or atrifluoromethyl groups) or an isobutyl group, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.26^(b)) The compounds according to any one of 1^(b)) to 17^(b)), whereinL^(3b) is represented by the formula (XXVI^(b)):

and R^(2b) is a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is unsubstitutedor substituted with a cyano group or a phenyl group), tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.27^(b)) The compounds according to any one of 1^(b)) to 17^(b)), whereinL^(3b) is represented by the formula (XXV^(b)):

(wherein R^(12b) is a hydrogen atom), and R^(2b) is a phenyl group or a5 to 6-membered aromatic heterocyclyl group (the phenyl group and the 5to 6-membered aromatic heterocyclyl group are unsubstituted orsubstituted with a C₁₋₃ alkyl group or a C₁₋₃ haloalkyl group),tautomers or pharmaceutically acceptable salts of the compounds orsolvates thereof.28^(b)) The compounds according to any one of 1^(b)) to 17^(b)), whereinL^(3b) is represented by the formula (XXVII^(b)):

and R^(2b) is a hydrogen atom or a C₁₋₃ alkyl group, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.29^(b)) The compounds according to any one of 1^(b)) to 17^(b)), whereinL^(3b) is represented by the formula (XXXII^(b)):

(wherein R^(12b) is a hydrogen atom, a C₁₋₃ alkyl group (the C₁₋₃ alkylgroup is unsubstituted or substituted with a substituent selected fromthe group consisting of a cyano group, a hydroxy group, a C₁₋₃ alkoxygroup, a C₃₋₆ cycloalkyl group and a phenyl group) or a C₁₋₃ haloalkylgroup), andR^(2b) is a hydrogen atom, a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group(the C₁₋₃ alkyl group and the C₁₋₃ haloalkyl group are unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of hydroxy groups,cyano groups, C₁₋₃ alkoxy groups, C₃₋₆ cycloalkyl groups, 4 to7-membered non-aromatic heterocyclyl groups, phenyl groups and 5 to6-membered aromatic heterocyclyl groups (the C₃₋₆ cycloalkyl groups, the4 to 7-membered non-aromatic heterocyclyl groups, the phenyl groups andthe 5 to 6-membered aromatic heterocyclyl groups are unsubstituted orsubstituted with a substituent selected from the group consisting of ahydroxy group, a halogen atom and a cyano group)), a C₃₋₆ cycloalkylgroup or a 4 to 7-membered non-aromatic heterocyclyl group (the C₃₋₆cycloalkyl group and the 4 to 7-membered non-aromatic heterocyclyl groupare unsubstituted or substituted with one or two identical or differentsubstituents independently selected from the group consisting of halogenatoms, cyano groups, C₁₋₃ alkyl groups, C₁₋₃ haloalkyl groups and C₁₋₆alkoxycarbonyl groups), tautomers or pharmaceutically acceptable saltsof the compounds or solvates thereof.30^(b)) The compounds according to any one of 1^(b)) to 17^(b)), whereinL^(3b) is represented by the formula (XXXV^(b)):

(wherein R^(12b) is a hydrogen atom, a C₁₋₃ alkyl group or a C₁₋₃haloalkyl group), and R^(2b) is a C₁₋₆ alkyl group (the C₁₋₆ alkyl groupis unsubstituted or substituted with a cyano group) or a C₁₋₆ haloalkylgroup, tautomers or pharmaceutically acceptable salts of the compoundsor solvates thereof.31^(b)) The compounds according to 1^(b)), wherein X^(b) is a nitrogenatom or CR^(15b) (wherein R^(15b) is a hydrogen atom or a halogen atom),Y^(b) is CR^(16b) (wherein R^(16b) is a hydrogen atom),R^(1b) is a hydrogen atom,the ring A^(b) is represented by any of the following formulae(XVIII^(b)-1) to (XVIII^(b)-8):

(wherein each of E^(2b) and E^(3b) is independently an oxygen atom or asulfur atom, and each of R^(4b), R^(5b), R^(6b), R^(8b) and R^(9b) isindependently a hydrogen atom or a C₁₋₃ alkyl group, and R^(10b) is ahydrogen atom, a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is unsubstitutedor substituted with one or two identical or different substituentsindependently selected from the group consisting of cyano groups,hydroxy groups, C₁₋₃ alkoxy groups, di-C₁₋₃ alkylamino groups, C₃₋₆cycloalkyl groups, 4 to 7-membered non-aromatic heterocyclyl groups,phenyl groups and 5 to 6-membered aromatic heterocyclyl groups (thephenyl group and the 5 to 6-membered aromatic heterocyclyl groups areunsubstituted or substituted with one or two identical or differentsubstituents independently selected from the group consisting of halogenatoms, C₁₋₃ alkyl groups and C₁₋₃ haloalkyl groups)), a C₁₋₆ haloalkylgroup, a C₃₋₆ cycloalkyl group, a 4 to 7-membered non-aromaticheterocyclyl group, a phenyl group or a 5 to 6-membered aromaticheterocyclyl group),the ring B^(b) is a C₃₋₁₁ cycloalkane, a 3 to 11-membered non-aromaticheterocycle, a C₆₋₁₄ aromatic carbocycle or a 5 to 10-membered aromaticheterocycle,L^(1b) is a single bond or a C₁₋₃ alkylene group,L^(2b) is a single bond, a C₁₋₆ alkylene group or a C₂₋₆ alkenylenegroup (the C₁₋₆ alkylene group and the C₂₋₆ alkenylene group areunsubstituted or substituted with one or more identical or differentsubstituents independently selected from the group consisting of halogenatoms, hydroxy groups, amino groups, cyano groups and nitro groups),n^(b) is 0 or 1,R^(3b) is a hydroxy group, an amino group, a carboxy group, a carbamoylgroup, a tetrazolyl group, a halogen atom, a cyano group, a nitro group,a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group, a C₃₋₆ cycloalkyl group, aC₁₋₃ alkoxy group, a C₁₋₃ haloalkoxy group or a C₁₋₃ alkylsulfonylgroup,L^(3b) is a simile bond or is represented by any of the followingformulae (VI^(b)-1) to (VI^(b)-11)

(wherein E^(1b) is an oxygen atom or a sulfur atom, and each of R^(12b)and R^(13b) is independently a hydrogen atom, a C₁₋₆ alkyl group or aC₁₋₆ haloalkyl group (the C₁₋₆ alkyl group and the C₁₋₆ haloalkyl groupare unsubstituted or substituted with one or two identical or differentsubstituents independently selected from the group consisting of cyanogroups, hydroxy groups, C₁₋₆ alkoxy groups, C₃₋₆ cycloalkyl groups, 4 to7-membered non-aromatic heterocyclyl groups, phenyl groups and 5 to6-membered aromatic heterocyclyl groups)), andwhen L^(3b) is a single bond, R^(2b) is a hydrogen atom, a halogen atom,a C₃₋₁₁ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclylgroup, a phenyl group, a naphthyl group, a 5 to 10-membered aromaticheterocyclyl group, a 8 to 11-membered partially saturated aromaticcyclic group or a 8 to 11-membered aromatic ring-condensed alicyclichydrocarbon group (the C₃₋₁₁ cycloalkyl group, the 3 to 11-memberednon-aromatic heterocyclyl group, the phenyl group, the naphthyl group,the 5 to 10-membered aromatic heterocyclyl group, the 8 to 11-memberedpartially saturated aromatic cyclic group and the 8 to 11-memberedaromatic ring-condensed alicyclic hydrocarbon group are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the substituent set V^(4b) and thesubstituent set V^(9b)), andwhen L^(3b) is not a single bond, R^(2b) is a hydrogen atom, a C₁₋₆alkyl group, a C₂₋₆ alkenyl group (the C₁₋₆ alkyl group and the C₂₋₆alkenyl group are unsubstituted or substituted with one or moreidentical or different substituents independently selected from thesubstituent set V^(6b) and the substituent set V^(9b)), a C₃₋₁₁cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclyl group, aC₆₋₁₄ aryl group, a 5 to 10-membered aromatic heterocyclyl group, a 8 to11-membered partially saturated aromatic cyclic group or a 8 to11-membered aromatic ring-condensed alicyclic hydrocarbon group (theC₃₋₁₁ cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclylgroup, the C₆₋₁₄ aryl group, the 5 to 10-membered aromatic heterocyclylgroup, the 8 to 11-membered partially saturated aromatic cyclic groupand the 8 to 11-membered aromatic ring-condensed alicyclic hydrocarbongroup are unsubstituted or substituted with one or more identical ordifferent substituents independently selected from the substituent setV^(4b) and the substituent set V^(9b)), tautomers or pharmaceuticallyacceptable salts of the compounds or solvates thereof.32^(b)) The compounds according to 1^(b)) or 31^(b)), wherein the ringA^(b) is represented by any of the following formulae (XXI^(b)-1) to(XXI^(b)-4):

(wherein E^(2b) and E^(3b) are oxygen atoms, R^(4b), R^(5b), R^(8b) andR^(9b) are hydrogen atoms, and R^(6b) is a hydrogen atom, a halogen atomor a C₁₋₃ alkyl group, and R^(10b) is a hydrogen atom, a C₁₋₆ alkylgroup (the C₁₋₆ alkyl group is unsubstituted or substituted with one ortwo identical or different substituents independently selected from thegroup consisting of cyano groups, hydroxy groups, C₁₋₃ alkoxy groups,C₁₋₃ alkylthio groups, di-C₁₋₃ alkylamino groups, di-C₁₋₃alkylaminocarbonyl groups, C₃₋₆ cycloalkyl groups and 4 to 7-memberednon-aromatic heterocyclyl groups), a C₁₋₆ haloalkyl group, a C₃₋₆cycloalkyl group or a 4 to 7-membered non-aromatic heterocyclyl group),tautomers or pharmaceutically acceptable salts of the compounds orsolvates thereof.33^(b)) The compounds according to 1^(b)), 31^(b)) or 32^(b)), whereinL^(1b) is a single bond,L^(2b) is a single bond, a C₁₋₆ alkylene group (the C₁₋₆ alkylene groupis unsubstituted or substituted with a hydroxy group or a cyano group)or a C₁₋₆ haloalkylene group, the ring B^(b) is a C₄₋₇ cycloalkane or a4 to 7-membered non-aromatic heterocycle,n^(b) is 0 or 1, andR^(3b) is a C₁₋₃ alkyl group, tautomers or pharmaceutically acceptablesalts of the compounds or solvates thereof.34^(b)) The compounds according to any one of 1^(b)) and 31^(b)) to33^(b)), wherein L^(3b) is a single bond, andR^(2b) is a hydrogen atom, a 4 to 7-membered non-aromatic heterocyclylgroup, a phenyl group, a 5 to 10-membered aromatic heterocyclyl group ora 8 to 11-membered partially saturated aromatic cyclic group (the 4 to7-membered non-aromatic heterocyclyl group, the phenyl group, the 5 to10-membered aromatic heterocyclyl group and the 8 to 11-memberedpartially saturated aromatic cyclic group are unsubstituted orsubstituted with one or more identical or different substituentsindependently selected from the group consisting of hydroxy groups,amino groups, carbamoyl groups, sulfamoyl groups, halogen atoms, cyanogroups, nitro groups, C₁₋₆ alkyl groups (the C₁₋₆ alkyl groups areunsubstituted or substituted with a cyano group), C₁₋₆ haloalkyl groups,C₃₋₁₁ cycloalkyl group, C₁₋₆ alkoxy groups, C₁₋₆ haloalkoxy groups, C₁₋₆alkylthio groups, C₁₋₆ haloalkylthio groups, C₁₋₆ alkylsulfonyl groups,C₁₋₆ haloalkylsulfonyl groups, C₁₋₆ alkoxycarbonyl groups, 4 to7-membered non-aromatic heterocyclyl groups, mono-C₁₋₆ alkylaminogroups, di-C₁₋₆ alkylamino groups, phenyl groups and 5 to 6-memberedaromatic heterocyclyl groups), tautomers or pharmaceutically acceptablesalts of the compounds or solvates thereof.35^(b)) The compounds according to any one of 1^(b)) and 31^(b)) to33^(b)), wherein L^(3b) is a single bond, andR^(2b) is a 8 to 11-membered partially saturated aromatic cyclic group(the 8 to 11-membered partially saturated aromatic cyclic group isunsubstituted or substituted with one or more identical or differenthalogen atoms independently selected from the group consisting offluorine atoms, chlorine atoms, bromine atoms and iodine atoms),tautomers or pharmaceutically acceptable salts of the compounds orsolvates thereof. 36^(b)) The compounds according to 34^(b)) or 35^(b)),wherein L^(2b) is a C₁₋₃ alkylene group, and the ring B^(b) iscyclohexane or piperidine, tautomers or pharmaceutically acceptablesalts of the compounds or solvates thereof.37^(b)) The compounds according to any one of 1^(b)) and 31^(b)) to33^(b)), wherein L^(3b) is represented by any of the following formulae(XIX^(b)-1) to (XIX^(b)-7):

(wherein E^(1b) is an oxygen atom, and R^(12b) is a hydrogen atom, aC₁₋₆ alkyl group (the C₁₋₆ alkyl group is unsubstituted or substitutedwith one or two identical or different substituents independentlyselected from the group consisting of cyano groups, hydroxy groups, C₁₋₃alkoxy groups, C₃₋₆ cycloalkyl groups and phenyl groups) or a C₁₋₆haloalkyl groups), andR^(2b) is a hydrogen atom, a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group(the C₁₋₆ alkyl group and the C₁₋₆ haloalkyl group are unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of cyano groups,hydroxy groups, C₃₋₆ cycloalkyl groups, 4 to 7-membered non-aromaticheterocyclyl groups, phenyl groups, 5 to 6-membered aromaticheterocyclyl groups and 8 to 11-membered partially saturated aromaticcyclic groups (the C₃₋₆ cycloalkyl groups, the 4 to 7-memberednon-aromatic heterocyclyl groups, the phenyl groups, the 5 to 6-memberedaromatic heterocyclyl groups and the 8 to 11-membered partiallysaturated aromatic cyclic group are unsubstituted or substituted withone or two identical or different substituents independently selectedfrom the group consisting of hydroxy groups, amino groups, halogenatoms, cyano groups, C₁₋₆ alkyl groups, C₁₋₃ haloalkyl groups, C₁₋₃alkoxy groups, C₁₋₃ haloalkoxy groups, C₁₋₃ alkylsulfonyl groups, C₁₋₃haloalkylsulfonyl groups, 4 to 7-membered non-aromatic heterocyclylgroup, phenyl groups, 5 to 6-membered aromatic heterocyclyl groups (thephenyl group and the 5 to 6-membered aromatic heterocyclyl group areunsubstituted or substituted with one or two identical or differentsubstituents independently selected from the substituent set V^(1b)),mono-C₁₋₆ alkylaminosulfonyl groups, di-C₁₋₆ alkylaminosulfonyl groupsand C₁₋₆ alkylsulfonylamino groups)), a C₃₋₆ cycloalkyl group, a 4 to7-membered non-aromatic heterocyclyl group, a phenyl group, a 5 to6-membered aromatic heterocyclyl group or a 8 to 11-membered partiallysaturated aromatic cyclic group (the C₃₋₆ cycloalkyl group, the 4 to7-membered non-aromatic heterocyclyl group, the phenyl group, the 5 to6-membered aromatic heterocyclyl group and the 8 to 11-memberedpartially saturated aromatic cyclic group are unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of hydroxy groups,amino groups, halogen atoms, cyano groups, C₁₋₆ alkyl groups, C₁₋₃haloalkyl groups, C₁₋₃ alkoxy groups, C₁₋₃ haloalkoxy groups, C₁₋₃alkylsulfonyl groups, C₁₋₃ haloalkylsulfonyl groups, 4 to 7-memberednon-aromatic heterocyclyl groups, phenyl groups, 5 to 6-memberedaromatic heterocyclyl groups (the phenyl groups and the 5 to 6-memberedaromatic heterocyclyl groups are unsubstituted or substituted with oneor more identical or different substituents independently selected fromthe substituent set V^(1b)), mono-C₁₋₆ alkylaminosulfonyl groups,di-C₁₋₆ alkylaminosulfonyl groups and C₁₋₆ alkylsulfonylamino groups),tautomers or pharmaceutically acceptable salts of the compounds orsolvates thereof.38^(b)) The compounds according to any one of 1^(b)),31^(b)) to 33^(b))and 37^(b)), wherein L^(3b) is represented by any of the followingformulae (XXX^(b)-1) to (XXX^(b)-3):

(wherein E^(1b) is an oxygen atom, and R^(12b) is a hydrogen atom), andR^(2b) is a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is unsubstituted orsubstituted with a substituent selected from the group consisting of acyano group, a C₃₋₆ cycloalkyl group, a phenyl group and a 5 to6-membered aromatic heterocyclyl group (the phenyl group and the 5 to6-membered aromatic heterocyclyl group are unsubstituted or substitutedwith one or two identical or different substituents independentlyselected from the group consisting of halogen atoms, cyano groups, C₁₋₆alkyl groups and C₁₋₃ haloalkyl groups)), a C₁₋₃ haloalkyl group, a C₃₋₆cycloalkyl group, a phenyl group or a 5 to 6-membered aromaticheterocyclyl group (the phenyl group and the 5 to 6-membered aromaticheterocyclyl group are unsubstituted or substituted with one or twoidentical or different substituents independently selected from thegroup consisting of halogen atoms, cyano groups, C₁₋₃ alkyl groups andC₁₋₃ haloalkyl groups), tautomers or pharmaceutically acceptable saltsof the compounds or solvates thereof.39^(b)) The compounds according to any one of 1^(b)) and 31^(b)) to33^(b)), wherein L^(3b) is represented by the formula (XXXII^(b)):

(wherein R^(12b) is a hydrogen atom, a C₁₋₃ alkyl group (the C₁₋₃ alkylgroup is unsubstituted or substituted with a substituent selected fromthe group consisting of a cyano group, a hydroxy group, a C₁₋₃ alkoxygroup, a C₃₋₆ cycloalkyl group and a phenyl group) or a C₁₋₃ haloalkylgroup), andR^(2b) is a hydrogen atom, a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group(the C₁₋₃ alkyl group and the C₁₋₃ haloalkyl group are unsubstituted orsubstituted with one or two identical or different substituentsindependently selected from the group consisting of hydroxy groups,cyano groups, C₁₋₃ alkoxy groups, C₃₋₆ cycloalkyl groups, 4 to7-membered non-aromatic heterocyclyl groups, phenyl groups and 5 to6-membered aromatic heterocyclyl groups (the C₃₋₆ cycloalkyl groups, the4 to 7-membered non-aromatic heterocyclyl groups, the phenyl groups andthe 5 to 6-membered aromatic heterocyclyl groups are unsubstituted orsubstituted with a substituent selected from the group consisting of ahydroxy group, a halogen atom, a cyano group and a C₁₋₃ haloalkylgroup)), a C₃₋₆ cycloalkyl group or a 4 to 7-membered non-aromaticheterocyclyl group (the C₃₋₆ cycloalkyl group and the 4 to 7-memberednon-aromatic heterocyclyl group are unsubstituted or substituted withone or two identical or different substituents independently selectedfrom the group consisting of halogen atoms, cyano groups, C₁₋₃ alkylgroups, C₁₋₃ haloalkyl groups and C₁₋₆ alkoxycarbonyl groups), tautomersor pharmaceutically acceptable salts of the compounds or solvatesthereof.40^(b)) The compounds according to any one of 1^(b)) and 31^(b)) to33^(b)), wherein L^(3b) is represented by the following formula(XXXVI^(b)-1) or (XXXVI^(b)-2):

(wherein R^(12b) is a hydrogen atom, a C₁₋₃ alkyl group (the C₁₋₃ alkylgroup is unsubstituted or substituted with a substituent selected fromthe group consisting of a cyano group, a hydroxy group, a C₁₋₃ alkoxygroup, a C₃₋₆ cycloalkyl group and a phenyl group) or a C₁₋₃ haloalkylgroup), and R^(2b) is a hydrogen atom, a C₁₋₃ alkyl group, a C₁₋₃haloalkyl group (the C₁₋₃ alkyl group and the C₁₋₃ haloalkyl group areunsubstituted or substituted with one or two identical or differentsubstituents independently selected from the group consisting of hydroxygroups, cyano groups, C₁₋₃ alkoxy groups, C₃₋₆ cycloalkyl groups, 4 to7-membered non-aromatic heterocyclyl groups, phenyl groups and 5 to6-membered aromatic heterocyclyl groups), a C₃₋₆ cycloalkyl group or a 4to 7-membered non-aromatic heterocyclyl group, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.41^(b)) The compounds according to 37^(b)) or 40^(b)), wherein L^(2b) isa single bond or a C₁₋₃ alkylene group, and the ring B^(b) is acyclohexane or piperidine, tautomers or pharmaceutically acceptablesalts of the compounds or solvates thereof.42^(b)) Compounds represented by the formula (XVII^(b)):

wherein X^(b) is CR^(15b) (wherein R^(15b) is a hydrogen atom, a halogenatom or a cyano group), and the rings A^(b) and B^(1b) are any of thefollowing combinations shown in Table^(b) 1, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.

The symbols in Table^(b) 1 denote the following substituents.

TABLE^(b) 1 A ^(b) B ^(1 b) A ^(b) B ^(1 b) A ^(b) B ^(1 b) A ^(b) B^(1 b) A 1 B ¹ 1 A 1 B ¹ 3 A 1 B ¹ 5 A 1 B ¹ 7 A 2 B ¹ 1 A 2 B ¹ 3 A 2 B¹ 5 A 2 B ¹ 7 A 3 B ¹ 1 A 3 B ¹ 3 A 3 B ¹ 5 A 3 B ¹ 7 A 4 B ¹ 1 A 4 B ¹3 A 4 B ¹ 5 A 4 B ¹ 7 A 5 B ¹ 1 A 5 B ¹ 3 A 5 B ¹ 5 A 5 B ¹ 7 A 6 B ¹ 1A 6 B ¹ 3 A 6 B ¹ 5 A 6 B ¹ 7 A 7 B ¹ 1 A 7 B ¹ 3 A 7 B ¹ 5 A 7 B ¹ 7 A8 B ¹ 1 A 8 B ¹ 3 A 8 B ¹ 5 A 8 B ¹ 7 A 1 B ¹ 2 A 1 B ¹ 4 A 1 B ¹ 6 A 1B ¹ 8 A 2 B ¹ 2 A 2 B ¹ 4 A 2 B ¹ 6 A 2 B ¹ 8 A 3 B ¹ 2 A 3 B ¹ 4 A 3 B¹ 6 A 3 B ¹ 8 A 4 B ¹ 2 A 4 B ¹ 4 A 4 B ¹ 6 A 4 B ¹ 8 A 5 B ¹ 2 A 5 B ¹4 A 5 B ¹ 6 A 5 B ¹ 8 A 6 B ¹ 2 A 6 B ¹ 4 A 6 B ¹ 6 A 6 B ¹ 8 A 7 B ¹ 2A 7 B ¹ 4 A 7 B ¹ 6 A 7 B ¹ 8 A 8 B ¹ 2 A 8 B ¹ 4 A 8 B ¹ 6 A 8 B ¹ 843 ^(b)) Compounds represented by the formula (XVII^(b)−1):

wherein X^(b) is CR^(15b) (wherein R^(15b) is a hydrogen atom, a halogenatom or a cyano group), and the rings A^(b) and B^(2b) are any of thefollowing combinations shown in Table^(b) 2, tautomers orpharmaceutically acceptable salts of the compounds or solvates thereof.

The symbols in Table^(b) 2 denote the following substituents.

TABLE^(a) 2 A^(b) B² ^(b) A^(b) B² ^(b) A^(b) B² ^(b) A^(b) B² ^(b) A1B²1 A1 B²3 A1 B²5 A1 B²7 A2 B²1 A2 B²3 A2 B²5 A2 B²7 A3 B²1 A3 B²3 A3B²5 A3 B²7 A4 B²1 A4 B²3 A4 B²5 A4 B²7 A5 B²1 A5 B²3 A5 B²5 A5 B²7 A6B²1 A6 B²3 A6 B²5 A6 B²7 A7 B²1 A7 B²3 A7 B²5 A7 B²7 A9 B²1 A9 B²3 A9B²5 A9 B²7 A1 B²2 A1 B²4 A1 B²6 A1 B²8 A2 B²2 A2 B²4 A2 B²6 A2 B²8 A3B²2 A3 B²4 A3 B²6 A3 B²8 A4 B²2 A4 B²4 A4 B²6 A4 B²8 A5 B²2 A5 B²4 A5B²6 A5 B²8 A6 B²2 A6 B²4 A6 B²6 A6 B²8 A7 B²2 A7 B²4 A7 B²6 A7 B²8 A9B²2 A9 B²4 A9 B²6 A9 B²844 ^(b)) The compounds with the combinations of substituents as definedin 42 ^(b)) or 43 ^(b)), wherein X^(b) is converted to a nitrogen atom,tautomers or pharmaceutically acceptable salts of the compounds orsolvates thereof.

The compounds of the present invention can be synthesized by theprocesses mentioned later, but the production of the compounds of thepresent invention is not restricted to these general examples.

The compounds of the present invention can usually be purified by columnchromatography, thin layer chromatography, high performance liquidchromatography (HPLC) or high performance liquid chromatography-massspectrometry (LC-MS) and, if necessary, they may be obtained with highpurity by recrystallization or washing with solvents.

In general, in the production of the compounds of the present invention,any solvents that are stable and inert under the reaction conditions anddo not hinder the reactions may be used without any particularrestrictions, and for example, sulfoxide solvents (such as dimethylsulfoxide), amide solvents (such as N,N-dimethylformamide orN,N-dimethylacetamide), ether solvents (such as diethyl ether,1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane or cyclopentyl methylether), halogenated solvents (such as dichloromethane, chloroform or1,2-dichloroethane), nitrile solvents (such as acetonitrile orpropionitrile), aromatic hydrocarbon solvents (such as benzene ortoluene), aliphatic hydrocarbon solvents (such as hexane or heptane),ester solvents (such as ethyl acetate), alcohol solvents (such asmethanol, ethanol, 1-propanol, 2-propanol or ethylene glycol) and watermay be mentioned. The reactions may be carried out in an arbitrarymixture of solvents mentioned above or in the absence of a solvent.

In general, in the production of the compounds of the present invention,the reaction temperature is chosen appropriately within the range offrom −78° C. to the boiling point of the solvent used for the reaction,and the production of the compounds of the present invention may becarried out at ordinary pressure or under pressure or with microwaveirradiation.

As acids generally used in the production of the compounds of thepresent invention, for example, organic acids (such as acetic acid,trifluoroacetic acid or p-toluenesulfonic acid) and inorganic acids(such as sulfuric acid or hydrochloric acid) may be mentioned.

As bases generally used in the production of the compounds of thepresent invention, for example, organic metal compounds (such asn-butyllithium, s-butyllithium, lithiumdiisopropylamide orisopropylmagnesium bromide), organic bases (such as triethylamine,N,N-diisopropylethylamine or N,N-dimethylaminopyridine) and inorganicbases (such as sodium carbonate, potassium carbonate, cesium carbonate,sodium hydroxide, potassium hydroxide or sodium hydride) may bementioned.

General processes for production of the compounds of the presentinvention are shown below, and the formulae of the intermediate and theend product in each step therein conceptually cover their protectedderivatives, too. Herein, protected derivatives are defined as compoundswhich can be converted to the desired product, if necessary, throughhydrolysis, reduction, oxidation, alkylation or the like and includecompounds protected with chemically acceptable protective groups.

Protection and deprotection may be carried out by generally knownprotection and deprotection reactions (for example, by referring toProtective Groups in Organic Synthesis, Fourth edition, T. W. Greene,John Wiley & Sons Inc. (2006)).

Hydrolysis, reduction and oxidation may be carried out by generallyknown functional group conversions (for example, by referring toComprehensive Organic Transformations, Second Edition, R. C. Larock,Wiley-VCH (1999)).

First, processes for producing the tricyclic pyrimidine compoundsrepresented by the formula (I^(a)) will be described.

Among the tricyclic pyrimidine compounds represented by the formula(I^(a)), the compounds (1a)-3 can be produced, for example, through thefollowing scheme (1a) (wherein R^(PR) is a hydrogen atom or a protectivegroup such as a Ts group, a TIPS group or a SEM group, and the othersymbols are the same as defined above).

A compound (1a)-1 can be converted to a compound (1a)-2 by using anequivalent or excessive amount of hydrazine or its equivalent in anappropriate solvent or in the absence of solvent at room temperature toa refluxing temperature.

A compound (1a)-2 can be converted to a compound (1a)-3 by using anequivalent or excessive amount of an oxidizing agent such as manganesedioxide or iodobenzenediacetate in an appropriate solvent or in theabsence of solvent at room temperature to a refluxing temperature. Thepresence of an acid or a base is sometimes effective for smooth progressof the reaction.

A compound (1a)-3 can also be obtained by using a compound (1a)-1 and anequivalent or excessive amount of tosylhydrazine or its equivalent in anappropriate solvent or in the absence of solvent at room temperature toa refluxing temperature. The presence of a base is sometimes effectivefor smooth progress of the reaction.

A compound (1a)-3 having a protective group as R^(PR) can be convertedto a compound (1a)-3 having a hydrogen atom as R^(PR) by deprotection.

Among the compounds represented by the formula (I^(a)), the compounds(2a)-2, (2a)-3 and (2a)-4 can be produced, for example, through thefollowing scheme (2a) (wherein E^(2a) is an oxygen atom or a sulfuratom, R^(PR) is a hydrogen atom or a protective group such as a Tsgroup, a TIPS group or a SEM group, and the other symbols are the sameas defined above).

A compound (2a)-1 can be converted to a compound (2a)-2 by using anequivalent or excessive amount of R^(4a)CHO, R^(4a)CO₂R^(Q),R^(4a)C(OR^(Q))₃, R^(4a)CONR^(Q) ₂ or R^(4a)C(OR^(Q))₂NR^(Q) ₂ (whereinR^(Q) is a hydrogen atom or a C₁₋₆ alkyl group) in an appropriatesolvent or in the absence of solvent at room temperature to a refluxingtemperature. Microwave irradiation or the presence of an acid or a baseis sometimes effective for smooth progress of the reaction.

A compound (2a)-1 can be converted to a compound (2a)-3 by using anequivalent or excessive amount of phosgene, phosgene dimer, phosgenetrimer, 1,1′-carbonyldiimidazole, dimethyl carbonate, carbon disulfideor 1,1′-thiocarbonyldiimidazole in an appropriate solvent or in theabsence of solvent at room temperature to a refluxing temperature. Thepresence of an acid or a base is sometimes effective for smooth progressof the reaction.

A compound (2a)-3 can be converted to a compound (2a)-4 by usingequivalent or excessive amounts of R^(6a)—R^(L) (wherein R^(L) is aleaving group such as a halogen atom, a methanesulfonyloxy group or ap-toluenesulfonyloxy group) and a base such as potassium carbonate orsodium hydride in an appropriate solvent or in the absence of solvent atroom temperature to a refluxing temperature.

A compound (2a)-3 or (2a)-4 having an oxygen atom as E^(2a) can beconverted to a compound (2a)-3 or (2a)-4 having a sulfur atom as E^(2a)by using an equivalent or excessive amount of a thiocarbonylationreagent such as phosphorus pentasulfide or Lawesson's reagent in anappropriate solvent or in the absence of solvent at −78° C. to arefluxing temperature.

Compounds (2a)-2, (2a)-3 and (2a)-4 having a protective group as R^(PR)can be converted to compounds (2a)-2, (2a)-3 and (2a)-4 having ahydrogen atom as R^(PR) by deprotection.

(Synthesis of Starting Materials 1a)

The compounds (3a)-3 and (3a)-6 can be produced, for example, throughthe following scheme (3a) (wherein X^(A) is a chlorine atom, a bromineatom or an iodine atom, each of R^(X) and R^(Y) is independently a C₁₋₆alkyl group, and R^(PR) is a hydrogen atom or a protective group such asa Ts group, a TIPS group or a SEM group, and the other symbols are thesame as defined above).

A compound (3a)-1 can be converted to a compound (3a)-3 by ametal-halogen exchange reaction using an equivalent or excessive amountof an organic metal reagent such as isopropylmagnesium chloride,2,6-dimethylphenylmagnesium bromide or n-butyllithium in an appropriatesolvent at −78° C. to room temperature followed by treatment with anequivalent or excessive amount of a compound (3a)-2 in an appropriatesolvent at −78° C. to room temperature.

A compound (3a)-1 can be converted to a compound (3a)-5 by ametal-halogen exchange reaction using an equivalent or excessive amountof an organic metal reagent such as isopropylmagnesium chloride,2,6-dimethylphenylmagnesium bromide or n-butyllithium in an appropriatesolvent at −78° C. to room temperature followed by treatment with anequivalent or excessive amount of a compound (3a)-4 in an appropriatesolvent at −78° C. to room temperature.

A compound (3a)-5 can be converted to a compound (3a)-3 by using anequivalent or excessive amount of an oxidizing agent such as manganesedioxide or 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one(Dess-Martin reagent) in an appropriate solvent at −78° C. to arefluxing temperature.

A compound (3a)-3 can be converted to a compound (3a)-6 by usingequivalent or excessive amounts of an amine reagent such as ammoniumacetate or hydroxylamine and a reducing agent such as sodiumtriacetoxyborohydride or zinc in an appropriate solvent or in theabsence of solvent at −78° C. to a refluxing temperature.

A compound (3a)-5 can be converted to a compound (3a)-6 by carrying outa reaction using equivalent or excessive amounts of phthalimide, aMitsunobu reagent and a phosphine reagent in an appropriate solvent orin the absence of solvent at −78° C. to a refluxing temperature,followed by deprotection. As a Mitsunobu reagent, diethylazodicarboxylate, diisopropyl azodicarboxylate or the like may bementioned, and as a phosphine reagent, triphenylphosphine,tributylphosphine or the like may be mentioned.

A compound (3a)-1 having a chlorine atom as X^(A) can be converted to acompound (3a)-1 having a bromine or iodine atom as X^(A) by using anequivalent or excessive amount of hydrobromic acid or hydroiodic acid inan appropriate solvent or in the absence of solvent at 0° C. to arefluxing temperature.

Compounds (3a)-3 and (3a)-6 having a protective group as R^(PR) can beconverted to compounds (3a)-3 and (3a)-6 having a hydrogen atom asR^(PR) by deprotection.

(Synthesis of Starting Materials 2a)

The compounds (4a)-2 can be produced, for example, through the followingscheme (4a) (wherein each of R^(X) and R^(Y) is independently a C₁₋₆alkyl group, and the other symbols are the same as defined above).

A compound (4a)-1 can be converted to a compound (4a)-2 by usingequivalent or excessive amounts of R^(Y)NH(OR^(X)) and a condensationagent such as dicyclohexycarbodiimide or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride in anappropriate solvent or in the absence of solvent at 0° C. to a refluxingtemperature. The presence of an acid or a base is sometimes effectivefor smooth progress of the reaction.

Among the compounds represented by the formula (I^(a)), the compounds(5a)-3, (5a)-4, (5a)-5 and (5a)-6 can be produced, for example, throughthe following scheme (5a) (wherein m is 0,1,2 or 3, R^(PR) is a hydrogenatom or a protective group such as a Ts group, a TIPS group or a SEMgroup, R^(PR2) is a protective group such as a Boc group or a Cbz group,E^(3a) is an oxygen atom or a sulfur atom, and the other symbols are thesame as defined above).

A compound (5a)-1 among the compounds (1a)-3 can be converted to acompound (5a)-2 by deprotection.

A compound (5a)-2 can be converted to a compound (5a)-3 by usingequivalent or excessive amounts of an electrophilic reagent representedby R^(2a)L^(3a)L^(2a)-R^(L) (wherein R^(L) is a leaving group such as ahalogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group)such as an alkyl halide, a methanesulfonate ester, an acid halide, asulfonyl chloride, a chloroformate and a base such as triethylamine inan appropriate solvent or in the absence of solvent at −78° C. to arefluxing temperature.

A compound (5a)-2 can be converted to a compound (5a)-3 by usingequivalent or excessive amounts of R^(2a)—CHO and a reducing agent suchas 2-picoline borane or sodium triacetoxyborohydride in an appropriatesolvent or in the absence of solvent at room temperature to a refluxingtemperature.

A compound (5a)-2 can be converted to a compound (5a)-4 by usingequivalent or excessive amounts of a compound (5a)-7 and a base such aspotassium carbonate or triethylamine in an appropriate solvent or in theabsence of solvent at −78° C. to a refluxing temperature.

A compound (5a)-2 can be converted to a compound (5a)-5 or/and (5a)-6 byusing equivalent or excessive amounts of a compound (5a)-8, a base suchas triethylamine and an acid catalyst such as ytterbium (111)trifluoromethanesulfonate in an appropriate solvent or in the absence ofsolvent at −78° C. to a refluxing temperature.

Compounds (5a)-3, (5a)-4, (5a)-5 and (5a)-6 having a protective group asR^(PR) can be converted to compounds (5a)-3, (5a)-4, (5a)-5 and (5a)-6having a hydrogen atom as R^(PR) by deprotection.

Among the compounds represented by the formula (I^(a)), the compounds(6a)-3, (6a)-4 and (6a)-5 can be produced, for example, through thefollowing scheme (6a) (wherein m is 0,1,2 or 3, R^(PR) is a hydrogenatom or a protective group such as a Ts group, a TIPS group or a SEMgroup, R^(PR3) is a protective group such as a benzyl group or an acetylgroup, and the other symbols are the same as defined above).

A compound (6a)-1 among the compounds (1a)-3 is converted to a compound(6a)-2 by deprotection.

A compound (6a)-2 can be converted to a compound (6a)-3 by using anequivalent or excessive amount of an oxidizing agent such as2-iodoxybenzoic acid or pyridinium chlorochromate in an appropriatesolvent or in the absence of solvent at −78° C. to a refluxingtemperature.

A compound (6a)-3 can be converted to a compound (6a)-4 by usingequivalent or excessive amounts of a compound (6a)-6 and a reducingagent such as 2-picoline borane or sodium triacetoxyborohydride in anappropriate solvent or in the absence of solvent at room temperature toa refluxing temperature.

A compound (6a)-2 can be converted to a compound (6a)-5 by usingequivalent or excessive amounts of an acidic alcohol represented byR^(2a)—OH such as phenol, a Mitsunobu reagent and a phosphine reagent inan appropriate solvent or in the absence of solvent at −78° C. to arefluxing temperature. As a Mitsunobu reagent, diethyl azodicarboxylate,diisopropyl azodicarboxylate or the like may be mentioned, and as aphosphine reagent, triphenylphosphine, tributylphosphine or the like maybe mentioned.

Compounds (6a)-3, (6a)-4 and (6a)-5 having a protective group as R^(PR)can be converted to compounds (6a)-3, (6a)-4 and (6a)-5 having ahydrogen atom as R^(PR) by deprotection.

Among the compounds represented by the formula (I^(a)), the compounds(7a)-3, (7a)-4, (7a)-5, (7a)-6, (7a)-7, (7a)-8 and (7a)-9 can beproduced, for example, through the following scheme (7a) (wherein m is0,1,2 or 3, R^(PR) is a hydrogen atom or a protective group such as a Tsgroup, a TIPS group or a SEM group, R^(PR3) is a protective group suchas a benzyl group or an acetyl group, R^(Z) is a hydrogen atom or a C₁₋₆alkyl group, X^(b) is a halogen atom, and the other symbols are the sameas defined above).

A compound (7a)-1 among the compounds (1a)-3 can be converted to acompound (7a)-2 by deprotection.

A compound (7a)-2 can be converted to a compound (7a)-3 by using anequivalent or excessive amount of an oxidizing agent such as2-iodoxybenzoic acid or pyridinium chlorochromate in an appropriatesolvent or in the absence of solvent at −78° C. to a refluxingtemperature.

A compound (7a)-3 can be converted to a compound (7a)-4 by usingequivalent or excessive amounts of a compound (7a)-10 and a reducingagent such as 2-picoline borane or sodium triacetoxyborohydride in anappropriate solvent or in the absence of solvent at room temperature toa refluxing temperature.

A compound (7a)-5 can be converted to a compound (7a)-4 by using anequivalent or excessive amount of a compound (7a)-10 in an appropriatesolvent or in the absence of solvent at −78° C. to a refluxingtemperature. The presence of a base is sometimes effective for smoothprogress of the reaction.

A compound (7a)-2 can be converted to a compound (7a)-5 by usingequivalent or excessive amounts of a halogenating agent and a phosphinereagent in an appropriate solvent or in the absence of solvent at −78°C. to a refluxing temperature. As a halogenating agent,N-bromosuccinimide, N,N-diethylaminosulfur trifluoride or the like maybe mentioned, and as a phosphine reagent, triphenylphosphine,tributylphosphine or the like may be mentioned.

A compound (7a)-5 can be converted to a compound (7a)-6 by using anequivalent or excessive amount of a compound (7a)-11 in an appropriatesolvent or in the absence of solvent at room temperature to a refluxingtemperature. The presence of an acid or a base is sometimes effectivefor smooth progress of the reaction.

A compound (7a)-2 can be converted to a compound (7a)-7 by usingequivalent or excessive amounts of an electrophilic reagent representedby R^(2a)—R^(L)(R^(L) is a leaving group such as a halogen atom, amethanesulfonyloxy group or a p-toluenesulfonyloxy group) such as analkyl halide, a methanesulfonyl ester or an acid halide and a base suchas potassium carbonate or sodium hydroxide in an appropriate solvent orin the absence of solvent at −78° C. to a refluxing temperature.

A compound (7a)-2 can be converted to a compound (7a)-7 by usingequivalent or excessive amounts of an acidic alcohol represented byR^(2a)—OH such as phenol, a Mitsunobu reagent and a phosphine reagent inan appropriate solvent or in the absence of solvent at −78° C. to arefluxing temperature. As a Mitsunobu reagent, diethyl azodicarboxylate,diisopropyl azodicarboxylate or the like may be mentioned, and as aphosphine reagent, triphenylphosphine, tributylphosphine or the like maybe mentioned.

A compound (7a)-2 can be converted to a compound (7a)-8 or (7a)-9 byusing equivalent or excessive amounts of R^(2a)C(═O)OH or R^(2a)(C═O)SH,a Mitsunobu reagent and a phosphine reagent in an appropriate solvent orin the absence of solvent at −78° C. to a refluxing temperature. AsR^(2a)C(═O)OH, acetic acid or the like may be mentioned, asR^(2a)(C═O)SH, thioacetic acid or the like may be mentioned. As aMitsunobu reagent, diethyl azodicarboxylate, diisopropylazodicarboxylate or the like may be mentioned, and as a phosphinereagent, triphenylphosphine, tributylphosphine or the like may bementioned.

Compounds (7a)-3, (7a)-4, (7a)-5, (7a)-6, (7a)-7, (7a)-8 and (7a)-9having a protective group as R^(PR) can be converted to compounds(7a)-3, (7a)-4, (7a)-5, (7a)-6, (7a)-7, (7a)-8 and (7a)-9 having ahydrogen atom as R^(PR) by deprotection.

Among the compounds represented by the formula (I^(a)), the compounds(8a)-2 and (8a)-3 can be produced, for example, through the followingscheme (8a) (wherein m is 0, 1, 2 or 3, R^(PR) is a hydrogen atom or aprotective group such as a Ts group, a TIPS group or a SEM group, andthe other symbols are the same as defined above).

A compound (8a)-1 among the compounds (7a)-2 can be converted to acompound (8a)-2 by using an equivalent or excessive amount of anoxidizing agent such as Jones reagent in an appropriate solvent or inthe absence of solvent at −78° C. to a refluxing temperature.

A compound (8a)-2 can be converted to a compound (8a)-3 by usingequivalent or excessive amounts of a compound (8a)-4 and a condensationagent such as N,N′-dicyclohexylcarbodiimide or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride in anappropriate solvent or in the absence of solvent at 0° C. to a refluxingtemperature. The presence of an acid or a base is sometimes effectivefor smooth progress of the reaction.

Compounds (8a)-2 and (8a)-3 having a protective group as R^(PR) can beconverted to compounds (8a)-2 and (8a)-3 having a hydrogen atom asR^(PR) by deprotection.

Among the compounds represented by the formula (I^(a)), the compounds(9a)-2 and (9a)-3 can be produced, for example, through the followingscheme (9a) (wherein m is 0, 1, 2 or 3, R^(PR) is a hydrogen atom or aprotective group such as a Ts group, a TIPS group or a SEM group, R^(Z)is a hydrogen atom or a C₁₋₆ alkyl group, and the other symbols are thesame as defined above).

A compound (9a)-1 among the compounds (7a)-9 can be converted to acompound (9a)-2 by using an equivalent or excessive amount of anoxidizing agent such as hydrogen peroxide in an appropriate solvent orin the absence of solvent at −78° C. to a refluxing temperature. Thepresence of an acid catalyst such as ammonium molybdate tetrahydrate issometimes effective for smooth progress of the reaction.

A compound (9a)-2 can be converted to a compound (9a)-3 by usingequivalent or excessive amounts of a compound (9a)-4 and a halogenatingagent such as thionyl chloride or phosphorus oxychloride in anappropriate solvent or in the absence of solvent at 0° C. to a refluxingtemperature. The presence of a base such as triethylamine is sometimeseffective for smooth progress of the reaction.

Compounds (9a)-2 and (9a)-3 having a protective group as R^(PR) can beconverted to compounds (9a)-2 and (9a)-3 having a hydrogen atom asR^(PR) by deprotection.

Among the compounds represented by the formula (I^(a)), the compounds(10a)-2 and (10a)-3 can be produced, for example, through the followingscheme (10a) (wherein m is 0, 1, 2 or 3, R^(PR) is a hydrogen atom or aprotective group such as a Ts group, a TIPS group or a SEM group, R⁷ isa hydrogen atom or a C₁₋₆ alkyl group, and the other symbols are thesame as defined above).

A compound (10a)-1 among the compounds (7a)-4 can be converted to acompound (10a)-2 by using an equivalent or excessive amount of an acidhalide in an appropriate solvent or in the absence of solvent at −78° C.to a refluxing temperature. The presence of a base is sometimeseffective for smooth progress of the reaction.

A compound (10a)-1 among the compounds (7a)-4 can be converted to acompound (10a)-3 by using an equivalent or excessive amount of asulfonyl halide in an appropriate solvent or in the absence of solventat −78° C. to a refluxing temperature. The presence of a base issometimes effective for smooth progress of the reaction.

Compounds (10a)-2 and (10a)-3 having a protective group as R^(PR) can beconverted to compounds (10a)-2 and (10a)-3 having a hydrogen atom asR^(PR) by deprotection.

Among the compounds represented by the formula (I^(a)), the compounds(11a)-2, (11a)-3, (11a)-4, (11a)-5, (11a)-6, (11a)-7, (11a)-8 and(11a)-9 can be produced, for example, through the following scheme (11a)(wherein m is 0, 1, 2 or 3, R^(PR) is a hydrogen atom or a protectivegroup such as a Ts group, a TIPS group or a SEM group, R^(Z) is ahydrogen atom or a C₁₋₆ alkyl group, R^(Z1) is a C₁₋₆ alkyl group, andthe other symbols are the same as defined above).

A compound (11a)-1 can be converted to a compound (11a)-2, (11a)-3 or(11a)-4 by using an equivalent or excessive amounts of a phosphoniumylide such as a Homer-Wadsworth-Emmons reagent and a base such as sodiumhydride in an appropriate solvent or in the absence of solvent at −78°C. to a refluxing temperature.

A compound (11a)-2, (11a)-4 or (11a)-3 can be converted to a compound(11a)-5, (11a)-6 or (11a)-7 respectively by using an equivalent orexcessive amount of a metal catalyst such as palladium-carbon catalystunder a hydrogen atmosphere in an appropriate solvent at −78° C. to arefluxing temperature.

A compounds (11a)-7 can be converted to a compounds (11a)-8 bydeprotection.

A compound (11a)-8 can be converted to a compound (11a)-9 by usingequivalent or excessive amounts of a compound (11a)-10 and acondensation agent such as N,N′-dicyclohexylcarbodiimide or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride in anappropriate solvent or in the absence of solvent at 0° C. to a refluxingtemperature. The presence of an acid or a base is sometimes effectivefor smooth progress of the reaction.

Compounds (11a)-2, (11a)-3, (11a)-4, (11a)-5, (11a)-6, (11a)-7, (11a)-8and (11a)-9 having a protective group as R^(PR) can be converted tocompounds (11a)-2, (11a)-3, (11a)-4, (11a)-5, (11a)-6, (11a)-7, (11a)-8and (11a)-9 having a hydrogen atom as R^(PR) by deprotection.

Among the compounds represented by the formula (I^(a)), the compounds(12a)-2, (12a)-3, (12a)-4 and (12a)-5 can be produced, for example,through the following scheme (12a) (wherein m is 0, 1, 2 or 3, R^(PR) isa hydrogen atom or a protective group such as a Ts group, a TIPS groupor a SEM group, R^(Z) is a hydrogen atom or a C₁₋₆ alkyl group, and theother symbols are the same as defined above).

A compound (12a)-1 among the compounds (7a)-3 can be converted to acompound (12a)-2 by using equivalent or excessive amounts of aphosphonium ylide such as a Horner-Wadsworth-Emmons reagent and a basesuch as sodium hydride in an appropriate solvent or in the absence ofsolvent at −78° C. to a refluxing temperature.

A compound (12a)-2 can be converted to a compound (12a)-3 by using anequivalent or excessive amount of a metal catalyst such aspalladium-carbon catalyst under a hydrogen atmosphere in an appropriatesolvent at −78° C. to a refluxing temperature.

A compound (12a)-1 can be converted to a compound (12a)-4 by usingequivalent or excessive amounts of malononitrile and a base such aspiperidine in an appropriate solvent or in the absence of solvent at−78° C. to a refluxing temperature.

A compound (12a)-4 can be converted to a compound (12a)-5 by using anequivalent or excessive amount of a metal catalyst such aspalladium-carbon catalyst under a hydrogen atmosphere in an appropriatesolvent at −78° C. to a refluxing temperature.

Compounds (12a)-2, (12a)-3, (12a)-4 and (12a)-5 having a protectivegroup as R^(PR) can be converted to compounds (12a)-2, (12a)-3, (12a)-4and (12a)-5 having a hydrogen atom as R^(PR) by deprotection.

Next, processes for producing the tricyclic pyridine compoundsrepresented by the formula (I^(b)) will be described.

Among the tricyclic pyridine compounds represented by the formula(I^(b)), the compounds (1 b)-2 can be produced, for example, through thefollowing scheme (1 b) (wherein R^(PR) is a hydrogen atom or aprotective group such as a Ts group, a TIPS group or a SEM group, andthe other symbols are the same as defined above).

A compound (1 b)-2 can be obtained by cyclization of a compound (1 b)-1.

A compound (1b)-1 can be converted to a compound (1b)-2 by using anequivalent or excessive amount of R^(8b)C(═O)R^(9b) orR^(8b)C(OR^(Q))₂R^(9b) (wherein R^(Q) is a hydrogen atom or a C₁₋₆ alkylgroup) in an appropriate solvent or in the absence of solvent at roomtemperature to a refluxing temperature. Microwave irradiation or thepresence of an acid catalyst such as acetic acid, trifluoroacetic acid,hydrochloric acid, sulfuric acid or p-toluenesulfonic acid is sometimeseffective for smooth progress of the reaction.

A compound (1b)-2 having a protective group as R^(PR) can be convertedto a compound having a hydrogen atom as R^(PR) by deprotection.

Among the compounds represented by the formula (I^(b)), the compounds(2b)-2 and (3b)-2 can be produced, for example, through the followingschemes (2b) and (3b) (wherein Y^(A) is an oxygen atom or a sulfur atom,R^(PR) is a hydrogen atom or a protective group such as a Ts group, aTIPS group or a SEM group, and the other symbols are the same as definedabove).

A compound (2b)-2 can be obtained by cyclization of a compound (2b)-1.

A compound (2b)-1 can be converted to a compound (2b)-2 by using anequivalent or excessive amount of R^(8b)CHO, R^(8b)CO₂R^(Q),R^(8b)C(OR^(Q))₃, R^(8b)CONR^(Q) ₂ or R^(8b)C(OR^(Q))₂NR^(Q) ₂ (whereinR^(Q) is a hydrogen atom or a C₁₋₆ alkyl group) in an appropriatesolvent or in the absence of solvent at room temperature to a refluxingtemperature. Microwave irradiation or the presence of an acid or a baseis sometimes effective for smooth progress of the reaction.

A compound (2b)-2 having an oxygen atom as Y^(A) can be converted to acompound (2b)-2 having a sulfur atom as Y^(A) by using an equivalent orexcessive amount of a thiocarbonylation agent such as phosphoruspentasulfide or Lawesson's reagent in an appropriate solvent or in theabsence of solvent at −78° C. to a refluxing temperature.

A compound (2b)-2 having a protective group as R^(PR) can be convertedto a compound having a hydrogen atom as R^(PR) by deprotection.

A corn pound (3b)-2 can be obtained by cyclization of a compound (3b)-1like the synthesis of a compound (2b)-2.

A compound (3b)-2 having a protective group as R^(PR) can be convertedto a compound having a hydrogen atom as R^(PR) by deprotection.

Among the compounds represented by the formula (I^(b)), the compounds(4b)-2, (4b)-3 and (4b)-4 can be produced, for example, through thefollowing scheme (4b) (wherein Y^(A) is an oxygen atom or a sulfur atom,R^(PR) is a hydrogen atom or a protective group such as a Ts group, aTIPS group or a SEM group, and the other symbols are the same as definedabove).

A compound (4b)-2 can be obtained by cyclization of a compound (4b)-1.

A compound (4b)-1 can be converted to a compound (4b)-2 by using anequivalent or excessive amount of phosgene, phosgene dimmer, phosgenetrimer, 1,1′-carbonyldiimidazole, dimethyl carbonate,1,1′-thiocarbonyldiimidazole, carbon disulfide or the like in anappropriate solvent at room temperature to a refluxing temperature. Thepresence of an acid or a base is sometimes effective for smooth progressof the reaction.

A compound (4b)-2 having hydrogen atoms as R^(5b) and R^(10b) can beconverted to a compound (4b)-3 by using a catalyst such aspalladium-carbon or manganese dioxide in an appropriate solvent at roomtemperature to a refluxing temperature.

A compound (4b)-2 or (4b)-3 having an oxygen atom as Y^(A) can beconverted to a compound (4b)-2 or (4b)-3 having a sulfur atom as Y^(A)by using a thiocarbonylation agent such as phosphorus pentasulfide orLawesson's reagent in an appropriate solvent or in the absence ofsolvent at −78° C. to a refluxing temperature.

A compound (4b)-2 or (4b)-3 having a protective group as R^(PR) can beconverted to a compound having a hydrogen atom as R^(PR) bydeprotection.

A compound (4b)-1 having a hydrogen atom as R^(10b) can be converted toa compound (4b)-4 by cyclization.

A compound (4b)-1 can be converted to a compound (4b)-4 by using anequivalent or excessive amount of R^(8b)CHO, R^(8b)CO₂R^(Q),R^(8b)C(OR^(Q))₃, R^(8b)CONR^(Q) ₂ or R^(8b)C(OR^(Q))₂NR^(Q) ₂ (whereinR^(Q) is a hydrogen atom or C₁₋₆ alkyl group) in an appropriate solventor in the absence of solvent at room temperature to a refluxingtemperature. Microwave irradiation or the presence of an acid or a baseis sometimes effective for smooth progress of the reaction.

A compound (4b)-4 having a protective group as R^(PR) can be convertedto a compound having a hydrogen atom as R^(PR) by deprotection.

Among the compounds represented by the formula (I^(b)), the compounds(5b)-2 can be produced, for example, through the following scheme (5b)(wherein Y^(A) is an oxygen atom or a sulfur atom, R^(PR) is a hydrogenatom or a protective group such as a Ts group, a TIPS group or a SEMgroup, and the other symbols are the same as defined above).

A compound (5b)-2 can be obtained by cyclization of a compound (5b)-1.

A compound (5b)-1 can be converted to a compound (5b)-2 by using anequivalent or excessive amount of R^(8b)CHO, R^(8b)CO₂R^(Q),R^(8b)C(OR^(Q))₃, R^(8b)CONR^(Q) ₂ or R^(8b)C(OR^(Q))₂NR^(Q) ₂ (whereinR^(Q) is a hydrogen atom or a C₁₋₆ alkyl group) in an appropriatesolvent or in the absence of solvent at room temperature to a refluxingtemperature. Microwave irradiation or the presence of an acid or a baseis sometimes effective for smooth progress of the reaction.

A compound (5b)-2 having an oxygen atom as Y^(A) can be converted to acompound having a sulfur atom as Y^(A) by using an equivalent orexcessive amount of a thiocarbonylation agent such as phosphoruspentasulfide or Lawesson's reagent in an appropriate solvent or in theabsence of solvent at −78° C. to a refluxing temperature.

A compound (5b)-2 having a protective group as R^(PR) can be convertedto a compound having a hydrogen atom as R^(PR) by deprotection.

Among the compounds represented by the formula (I^(b)), the compounds(6b)-2 and (6b)-3 can be produced, for example, through the followingscheme (6b) (wherein X^(b) is a bromine atom or an iodine atom, R^(PR)is a hydrogen atom or a protective group such as a Ts group, a TIPSgroup or a SEM group, and the other symbols are the same as definedabove).

A compound (6b)-3 can be obtained by bromination or iodination of acompound (6b)-1 followed by cyanization of the resulting compound(6b)-2.

A compound (6b)-1 can be converted to a compound (6b)-2 by using anequivalent or excessive amount of a halogenating agent such as bromine,iodine, N-bromosuccinimide or N-iodosuccinimide in an appropriatesolvent or in the absence of solvent at −78° C. to a refluxingtemperature.

A compound (6b)-2 can be converted to a compound (6b)-3 by using anequivalent or excessive amount of a metal cyanide such as copper cyanideor zinc cyanide in the presence of a palladium catalyst such astetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) dichloride in an appropriatesolvent or in the absence of solvent at room temperature to a refluxingtemperature.

A compound (6b)-2 or (6b)-3 having a protective group as R^(PR) can beconverted to a compound having a hydrogen atom as R^(PR) bydeprotection.

(Synthesis of Starting Materials 1 b)

The compounds (7b)-2 can be produced, for example, through the followingscheme (7b) (wherein R^(L) is a leaving group such as a chlorine atom, amethanesulfonyloxy group or a p-toluenesulfonyloxy group, R^(PR) is ahydrogen atom or a protective group such as a Ts group, a TIPS group ora SEM group, and the other symbols are the same as defined above).

A compound (7b)-2 can be obtained by a Mitsunobu reaction of a compound(7b)-1 with R^(10b)R^(PR1) NH (wherein R^(PR1) is a protective groupsuited for a Mitsunobu reaction such as a methanesulfonyl group or ap-toluenesulfonyl group) following by deprotection.

A compound (7b)-1 can be converted to a compound (7b)-2 by usingequivalent or excessive amounts of R^(10b)R^(PR1)NH, a Mitsunobu reagentand a phosphine reagent in an appropriate solvent or in the absence ofsolvent at −78° C. to a refluxing temperature, followed by deprotection.As a Mitsunobu reagent, diethyl azodicarboxylate, diisopropylazodicarboxylate or the like may be mentioned, and as a phosphinereagent, triphenylphosphine, tributylphosphine or the like may bementioned. A compound (7b)-2 having a hydrogen atom as R^(10b) can beobtained by a similar reaction using phthalimide instead ofR^(10b)R^(PR1) NH followed by deprotection.

A compound (7b)-2 can be obtained by conversion of a compound (7b)-1 toa compound (7b)-3 having a leaving group R^(L) followed by asubstitution reaction using R^(10b)NH₂.

A compound (7b)-1 can be converted to a compound (7b)-3 by using anequivalent or excessive amount of phosphorus oxychloride, thionylchloride, methanesulfonyl chloride, p-toluenesulfonyl chloride or thelike in an appropriate solvent or in the absence of solvent at −78° C.to a refluxing temperature. The presence of a base is sometimeseffective for smooth progress of the reaction.

A compound (7b)-3 can be converted to a compound (7b)-2 by using anequivalent or excessive amount of R^(10b)NH₂ in an appropriate solventor in the absence of solvent at −78° C. to a refluxing temperature.Microwave irradiation or the presence of a base is sometimes effectivefor smooth progress of the reaction.

(Synthesis of Starting Materials 2b)

The compounds (8b)-3 can be produced, for example, through the followingscheme (8b) (wherein R^(PR) is a hydrogen atom or a protective groupsuch as a Ts group, a TIPS group or a SEM group, and the other symbolsare the same as defined above).

A compound (8b)-3 can be obtained by oxidation of a compound (8b)-1followed by condensation of the resulting compound (8b)-2.

A compound (8b)-1 can be converted to a compound (8b)-2 by using anequivalent or excessive amount of a oxidizing agent such as potassiumpermanganate or sodium chlorite in an appropriate solvent or in theabsence of solvent at room temperature to a refluxing temperature.

A compound (8b)-2 can be converted to a compound (8b)-3 by usingequivalent or excessive amounts of ammonia-methanol or its equivalentand a condensation agent such as N,N′-dicyclohexylcarbodiimide or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride in anappropriate solvent or in the absence of solvent at 0° C. to a refluxingtemperature. The presence of a catalyst such as N-hydroxybenzotriazoleor a base is sometimes effective for smooth progress of the reaction.

(Synthesis of Staring Materials 3b)

The compounds (9b)-2 and (9b)-3 can be produced, for example, throughthe following scheme (9b) (wherein R^(PR) is a hydrogen atom or aprotective group such as a Ts group, a TIPS group or a SEM group, andthe other symbols are the same as defined above).

A compound (9b)-2 can be obtained by an addition reaction of a compound(9b)-1.

A compound (9b)-1 can be converted to a compound (9b)-2 by using anequivalent or excessive amount of an addition reaction reagent in asolvent inert to the reaction at −78° C. to a refluxing temperature. Asan addition reaction reagent, a hydride reducing agent such as sodiumborohydride or diisobutylaluminum hydride or a metal reagent such asmethyllithium or phenylmagnesium bromide may be mentioned.

A compound (9b)-3 can be obtained by reductive N-alkylation of acompound (9b)-1 through formation of an imine.

A compound (9b)-1 can be converted to a compound (9b)-3 by usingequivalent or excessive amounts of R^(10b)NH₂ and a hydride reducingagent such as sodium cyanoborohydride or sodium triacetoxyborohydride inan appropriate solvent or in the absence of solvent at 0° C. to arefluxing temperature. Microwave irradiation or the presence of an acidis sometimes effective for smooth progress of the reaction. A compoundhaving a hydrogen atom as R^(10b) can be obtained by using hydroxylamineor its equivalent instead of R^(10b)NH₂ and lithium aluminum hydride,zinc or a hydrogen atmosphere containing palladium-carbon as a reducingagent.

(Synthesis of Starting Materials 4b)

The compounds (10b)-3, (11b)-3 and (12b)-3 can be produced, for example,through the following schemes (10b), (11 b) and (12b) (wherein R^(PR) isa hydrogen atom or a protective group such as a Ts group, a TIPS groupor a SEM group, and the other symbols are the same as defined above).

A compound (10b)-1 can be converted to a compound (10b)-3 by using anequivalent or excessive amount of an amine derivative (10b)-2 in anappropriate solvent or in the absence of solvent at room temperature toa refluxing temperature. The substituent reaction is preferred to becarried out under microwave irradiation or sometimes in the presence ofa base or may be carried out under the reaction conditions used for theBuchwald-Hartwig reaction (for example, by referring to AdvancedSynthesis & Catalysis, 2004, 346, pp. 1599-1626). It is possible toappropriately combine tris(dibenzylideneacetone)dipalladium (0),tetrakis(triphenylphosphine)palladium(0), palladium (II) acetate or thelike with 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos),2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos) or thelike, without particular restrictions.

Compounds (11b)-3 and (12b)-3 can be obtained by using a compound(11b)-1 and an amine derivative (11b)-2 or a compound (12b)-1 and anamine derivative (12b)-2, like a compound (10b)-3.

(Synthesis of Starting Materials 5b)

The compounds (13b)-4 can be produced, for example, through thefollowing scheme (13b) (wherein R^(PR) is a hydrogen atom or aprotective group such as a Ts group, a TIPS group or a SEM group, R^(Q)is a hydrogen atom or a C₁₋₆ alkyl group, and the other symbols are thesame as defined above).

A compound (13b)-4 can be obtained by the Stille reaction of compounds(13b)-2 and (13b)-3 (for example, by referring Bulletin of the ChemicalSociety of Japan, 1987, 60, pp. 767-768).

A compound (13b)-2 can be converted to a compound (13b)-4 by using anequivalent or excessive amount of a compound (13b)-3 in the presence ofa palladium catalyst such as tetrakis(triphenylphosphine)palladium (0),bis(triphenylphosphine)palladium (II) dichloride orbis(acetonitrile)palladium (II) dichloride in an appropriate solvent orin the absence of solvent at room temperature to a refluxingtemperature. The presence of an acid or a base is sometimes effectivefor smooth progress of the reaction.

A compound (13b)-2 can be obtained by oxidization of a compound (13b)-1followed by a reaction of the resulting N-oxide derivative with achlorination agent.

A compound (13b)-1 can be converted to a compound (13b)-2 by oxidationwith an equivalent or excessive amount of an oxidizing agent such asm-chloroperbenzoic acid, peracetic acid or aqueous hydrogen peroxide inan appropriate solvent or in the absence of solvent at 0° C. to arefluxing temperature, followed by a reaction of the resulting N-oxidederivative with an equivalent or excessive amount of a chlorinationagent such as phosphorus oxychloride or methanesulfonyl chloride in anappropriate solvent or in the absence of solvent at room temperature toa refluxing temperature.

(Synthesis of Starting Materials 6b)

The compounds (14b)-3 and (14b)-5 can be produced, for example, throughthe following scheme (14b) (wherein R^(PR) is a hydrogen atom or aprotective group such as a Ts group, a TIPS group or a SEM group, andthe other symbols are the same as defined above).

Compounds (14b)-3 and (14b)-4 can be obtained by coupling of an anionformed from a compound (14b)-2.

A compound (14b)-2 can be converted to a compound (14b)-3 by lithiationusing an equivalent or excessive amount of an organic metal reagent suchas n-butyllithium or s-butyllithium in an appropriate solvent or in theabsence of solvent at −78° C. to room temperature followed by couplingwith an electrophilic reagent such as N,N-, dimethylformamide,R^(4b)CO₂R^(Q), R^(4b)CONR^(Q) ₂ or R^(4b)C(O)N(OR^(Q))R^(Q) (whereinR^(Q) is a hydrogen atom or a C₁₋₆ alkyl group).

A compound (14b)-2 can be converted to a compound (14b)-4 by lithiationusing an equivalent or excessive amount of an organic metal reagent suchas n-butyllithium or s-butyllithium in an appropriate solvent or in theabsence of solvent at −78° C. to room temperature followed by couplingwith an electrophilic reagent such as (R^(6b)CH₂S)₂.

A compound (14b)-4 can be converted to a compound (14b)-5 by using anequivalent or excessive amount of an oxidizing agent such asm-chloroperbenzoic acid, peracetic acid or aqueous hydrogen peroxide inan appropriate solvent or in the absence of solvent at 0° C. to arefluxing temperature.

A compound (14b)-1 can be converted to a compound (14b)-2 by oxidationwith an equivalent or excessive amount of an oxidizing agent such asm-chloroperbenzoic acid, peracetic acid or aqueous hydrogen peroxide inan appropriate solvent or in the absence of solvent at 0° C. to arefluxing temperature, followed by a reaction of the resulting N-oxidederivative with an equivalent or excessive amount of a chlorinationagent such as phosphorus oxychloride or methanesulfonyl chloride in anappropriate solvent or in the absence of solvent at room temperature toa refluxing temperature.

(Synthesis of Starting Materials 7b)

The compounds (15b)-4 can be produced, for example, through thefollowing scheme (15b) (wherein R^(PR) is a hydrogen atom or aprotective group such as a Ts group, a TIPS group or a SEM group).

A compound (15b)-4 can be obtained by bromination or iodination of acompound (15b)-2 followed by dehydrogenation of the resulting compound(15b)-3.

A compound (15b)-3 can be converted to a compound (15b)-4 by using acatalyst such as palladium-carbon or manganese dioxide in an appropriatesolvent or in the absence of solvent at room temperature to a refluxingtemperature.

A compound (15b)-2 can be converted to a compound (15b)-3 by using anequivalent or excessive amount of a halogenating agent such as bromine,N-bromosuccinimide, iodine or N-iodosuccinimide in an appropriatesolvent or in the absence of solvent at 0° C. to a refluxingtemperature.

A compound (15b)-1 can be converted to a compound (15b)-2 in thepresence of a palladium-carbon catalyst under a hydrogen atmosphere inan appropriate solvent or in the absence of solvent at room temperatureto a refluxing temperature.

(Synthesis of Starting Materials 8b)

The compounds (16b)-2 can be produced, for example, through thefollowing scheme (16b).

A compound (16b)-1 can be converted to a compound (16b)-2 by using anequivalent or excessive amount of R^(16b)CO₂R^(Q) or R^(16b)C(OR^(Q))₃(wherein R^(Q) is a hydrogen atom or a C₁₋₆ alkyl group) in anappropriate solvent or in the absence of solvent at room temperature toa refluxing temperature.

For synthesis of 7-azaindole or 1-deazapurine, the following generalmethods may be referred to.

As general methods for synthesis of 7-azaindole, those disclosed inCurrent Organic Chemistry, 2001, 5, pp. 471-506 are known.

As general methods for synthesis of 1-deazapurine, those disclosed inShin-pen Hetero-kan Kagoubutsu Ouyou-hen (Kodansha, 2004) pp. 233-251are known.

(Synthesis of Starting Materials 9b)

The amine compounds (17b)-1 can be produced from the correspondingnitrile compounds, acid amide compounds, oxime compounds, halogencompounds, ketone compounds, aldehyde compounds, alcohol compounds,boron compounds, epoxide compounds, acid imide compounds and carbamatecompounds (for example, by referring to Jikken Kagaku Koza vol. 20 YukiGosei II, edited by the Chemical Society of Japan, published by MARUZENCo., Ltd., 1992; Bioorganic & Medicinal Chemistry, 13, 4022, 2005,Kuramochi T. et al.; Journal of Medicinal Chemistry, 50, 149, 2007;Journal of Organic Chemistry, 46, 4296, 1981; Journal of OrganicChemistry, 44, 2081, 1979; Acta Chemica Scandinavica, 19, 1741, 1965;and Organic Letters, 5, 4497, 2003).

Among the compounds represented by the formula (I^(b)), the compounds(18b)-2 and (18b)-3 can be produced, for example, through the followingscheme (18b) (wherein R^(PR) is a hydrogen atom or a protective groupsuch as a Ts group, a TIPS group or a SEM group, and the other symbolsare the same as defined above).

A compound (18b)-3 can be obtained by cyclization of a compound (18b)-1followed by a substitution reaction of the resulting compound (18b)-2.

A compound (18b)-1 can be converted to a compound (18b)-2 by using anequivalent or excessive amount of phosgene, phosgene dimer, phosgenetrimer, 1,1′-carbonyldiimidazole, dimethyl carbonate,1,1′-thiocarbonyldiimidazole, carbon disulfide or the like in anappropriate solvent or in the absence of solvent at room temperature toa refluxing temperature. The presence of an acid or a base or microwaveirradiation is sometimes effective for smooth progress of the reaction.

A compound (18b)-2 can be converted to a compound (18b)-3 by using anequivalent or excessive amount of an electrophilic reagent representedby R^(10b)-R^(L) (wherein R^(L) is a leaving group such as a chlorineatom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group) suchas an alkyl halide, an alkyl mesylate or an aryl halide in the presenceof a base such as triethylamine in an appropriate solvent or in theabsence of solvent at room temperature to a refluxing temperature.Microwave irradiation is sometimes effective for smooth progress of thereaction. A compound (18b)-2 can also be converted to a compound (18b)-3by using equivalent or excessive amounts of a primary or secondaryalcohol, a Mitsunobu reagent and a phosphine reagent in an appropriatesolvent or in the absence of solvent at −78° C. to a refluxingtemperature. As a Mitsunobu reagent, diethyl azodicarboxylate,diisopropyl azodicarboxylate or the like may be mentioned, and as aphosphine reagent, triphenylphosphine, tributylphosphine or the like maybe mentioned.

A compound (18b)-2 or (18b)-3 having an oxygen atom as Y^(A) can beconverted to a compound (18b)-2 or (18b)-3 having a sulfur atom as Y^(A)by using an equivalent or excessive amount of a thiocarbonylation agentsuch as phosphorus pentasulfide or Lawesson's reagent in an appropriatesolvent or in the absence of solvent at −78° C. to a refluxingtemperature.

A compound (18b)-2 or (18)-3 having a protective group as R^(PR) can beconverted to a compound having a hydrogen atom as R^(PR) bydeprotection.

Among the compounds represented by the formula (I^(b)), the compounds(19b)-2 and (19b)-3 can be produced, for example, through the followingscheme (19b) (wherein R^(PR) is a hydrogen atom or a protective groupsuch as a Ts group, a TIPS group or a SEM group, R^(PR2) is a benzyltype protective group such as a benzyl group or a benzyloxycarbonylgroup, m is 0-3, and the other symbols are the same as defined above).

A compound (19b)-3 can be obtained by deprotection of the R^(PR2) in acompound (19b)-1 among the compounds (2b)-2 followed by a substitutionreaction of the resulting compound (19b)-2.

A compound (19b)-1 having a benzyl type protective group as R^(PR2) canbe converted to a compound (19b)-2 by using a catalytic amount ofpalladium-carbon under a hydrogen atmosphere in an appropriate solventat room temperature to a refluxing temperature. The presence of an acidis sometimes effective for smooth progress of the reaction.

A compound (19b)-2 can be converted to a compound (19b)-3 by usingequivalent or excessive amounts of an electrophilic reagent representedby R^(2b)L^(3b)L^(2b)-R^(L) (wherein R^(L) is a leaving group such as ahalogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxygroup) such as an alkyl halide, an acid chloride, a sulfonyl chloride, achloroformate ester, an isocyanate or an isothiocyanate and a base suchas triethylamine in an appropriate solvent or in the absence of solventat −78° C. to a refluxing temperature. A compound (19b)-2 can also beconverted to a compound (19b)-3 by using an equivalent or excessiveamount of an aldehyde or a ketone in the presence of a hydride reducingagent such as sodium cyanoborohydride or 2-picoline borane in anappropriate solvent or in the absence of solvent at 0° C. to a refluxingtemperature. Microwave irradiation or the presence of an acid issometimes effective for smooth progress of the reaction.

A compound (19b)-3 having a protective group as R^(PR) can be convertedto a compound having a hydrogen atom as R^(PR) by deprotection.

Among the compounds represented by the formula (I^(b)), the compounds(20b)-2 and (20b)-3 can be produced, for example, through the followingscheme (20b) (wherein R^(PR) is a hydrogen atom or a protective groupsuch as a Ts group, a TIPS group or a SEM group, R^(PR2) is a benzyltype protective group such as a benzyl group or a benzyloxycarbonylgroup, m is 0, 1, 2 or 3 and the other symbols are the same as definedabove).

A compound (20b)-3 can be obtained by deprotection of the R^(PR2) in acompound (20b)-1 among the compounds (18b)-3 followed by a substitutionreaction of the resulting compound (20b)-2.

A compound (20b)-1 having a benzyl type protective group as R^(PR2) canbe converted to a compound (20b)-2 by using a catalytic amount ofpalladium-carbon under a hydrogen atmosphere in an appropriate solventat room temperature to a refluxing temperature. The presence of an acidis sometimes effective for smooth progress of the reaction.

A compound (20b)-2 can be converted to a compound (20b)-3 by usingequivalent or excessive amounts of an electrophilic reagent representedby R^(2b)L^(3b)L^(2b)-R^(L) (wherein R^(L) is a leaving group such as ahalogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxygroup) such as an alkyl halide, an acid chloride, sulfonyl chloride, achloroformate, an isocyanate or an isothiocyanate and a base such astriethylamine in an appropriate solvent or in the absence of solvent at−78° C. to a refluxing temperature. A compound (20b)-2 can also beconverted to a compound (20b)-3 by using an equivalent or excessiveamount of an aldehyde or a ketone in the presence of a reducing agentsuch as sodium cyanoborohydride or 2-picoline borane in an appropriatesolvent or in the absence of solvent at 0° C. to a refluxingtemperature. Microwave irradiation or the presence of an acid issometimes effective for smooth progress of the reaction.

A compound (20b)-3 having a protective group as R^(PR) can be convertedto a compound having a hydrogen atom as R^(PR) by deprotection.

Among the compounds represented by the formula (I^(b)), the compounds(21 b)-2, (21b)-3 and (21b)-4 can be produced, for example, through thefollowing scheme (21b) (wherein R^(PR) is a hydrogen atom or aprotective group such as a Ts group, a TIPS group or a SEM group,R^(PR5) is a protective group such as a benzyl group or an acetyl group,R^(Z) is a hydrogen atom or a C₁₋₆ alkyl group, m is 0, 1, 2 or 3, andthe other symbols are the same as defined above).

A compound (21b)-1 among the compounds (18b)-3 is converted to acompound (21b)-2 by deprotection.

A compound (21 b)-2 can be converted to a compound (21 b)-3 by oxidationwith an equivalent or excessive amount of an oxidizing agent such as2-iodoxybenzoic acid or pyridinium chlorochromate in an appropriatesolvent or in the absence of solvent at −78° C. to a refluxingtemperature.

A compound (21b)-3 can be converted to a compound (21b)-4 by usingequivalent or excessive amounts of a compound (21 b)-5 and a reducingagent such as 2-picoline borane or sodium triacetoxyborohydride in anappropriate solvent or in the absence of solvent at room temperature toa refluxing temperature.

Compounds (21b)-3 and (21b)-4 having a protective group as R^(PR) can beconverted to compounds (21 b)-3 and (21 b)-4 having a hydrogen atom asR^(PR) by deprotection.

In the present invention, the tricyclic pyrimidine compounds of thepresent invention represented by the formula (I^(a)) and the tricyclicpyridine compounds of the present invention represented by the formula(I^(b)) may be present in the form of tautomers or geometrical isomerswhich undergo endocyclic or exocyclic isomerization, mixtures oftautomers or geometric isomers or mixtures of thereof. When thecompounds of the present invention have an asymmetric center, whether ornot resulting from an isomerization, the compounds of the presentinvention may be in the form of resolved optical isomers or in the formof mixtures containing them in certain ratios. Further, when thecompounds of the present invention have two or more asymmetric centers,the compounds of the present invention can be in the form ofdiastereomers due to optical isomerism about them. The compounds of thepresent invention may be in the form of a mixture of all these isomersin certain ratios. For example, diastereomer can be separated bytechniques well known to those skilled in the art such as fractionalcrystallization, and optical isomers can be obtained by techniques wellknown in the field of organic chemistry for this purpose.

The tricyclic pyrimidine compounds of the present invention representedby the formula (I^(a)) and the tricyclic pyridine compounds of thepresent invention represented by the formula (I^(b)) or pharmaceuticallyacceptable salts thereof may be in the form of arbitrary crystals orarbitrary hydrates, depending on the production conditions. The presentinvention covers these crystals, hydrates and mixtures. They may be inthe form of solvates with organic solvents such as acetone, ethanol,1-propanol and 2-propanol, and the present invention covers any of theseforms.

The present invention covers pharmaceutically acceptable salts of thecompounds of the present invention represented by the formulae (I^(a))and (I^(b)).

The compounds of the present invention represented by the formulae(I^(a)) and (I^(b)) may be converted to pharmaceutically acceptablesalts or may be liberated from the resulting salts, if necessary. Thepharmaceutically acceptable salts of the present invention may be, forexample, salts with alkali metals (such as lithium, sodium andpotassium), alkaline earth metals (such as magnesium and calcium),ammonium, organic bases, amino acids, inorganic acids (such ashydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid)and organic acids (such as acetic acid, citric acid, maleic acid,fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acidand p-toluenesulfonic acid).

The present invention covers prodrugs of the compounds of the presentinvention represented by the formulae (I^(a)) and (I^(b)).

Prodrugs are derivatives of medicinal compounds having chemically ormetabolically degradable groups and give pharmacologically activemedicinal compounds upon solvolysis or under physiological conditions invivo. Methods for selecting or producing appropriate prodrugs aredisclosed in, for example, Design of Prodrugs (Elsevier, Amsterdam1985). In the present invention, in the case of a compound having ahydroxy group, prodrugs like acyloxy derivatives obtained by reactingthe compound with appropriate acyl halides, appropriate acid anhydridesor appropriate haloalkoxycarbonyl compounds may, for example, bementioned. Structures particularly preferred as prodrugs include—OCOC₂H₅, —OCO(t-Bu), —OCOC₁₅H₃₁, —OCO(m-CO₂Na-Ph), —OCOCH₂CH₂CO₂Na,—OCOCH(NH₂)CH₃, —OCOCH₂N(CH₃)₂, —O—CH₂OC(═O)CH₃ or the like. In the caseof a compound having an amino group, prodrugs obtained by reacting thecompound having an amino group with appropriate acid halides,appropriate mixed acid anhydrides or haloalkoxycarbonyl compounds may,for example, be mentioned. Structures particularly preferred as prodrugsinclude —NHCO(CH₂)₂₀OCH₃, —NHCOCH(NH₂)CH₃, —NH—CH₂O(C═O)CH₃ or the like.

The JAK inhibitors and the preventive, therapeutic and/or improvingagents for diseases against which inhibition of JAK is effective arethose mentioned below among the tricyclic pyrimidine compounds and thetricyclic pyridine compounds of the present invention.

1) JAK inhibitors containing the compounds as defined in any one of1^(a)) to 62^(a)) and 1^(b)) to 44^(b)), tautomers or pharmaceuticallyacceptable salts of the compounds or solvates thereof, as an activeingredient.2) Preventive, therapeutic or improving agents for diseases againstwhich inhibition of JAK is effective, which contains the JAK inhibitorsas defined in 1) as an active ingredient.3) Therapeutic agents for rheumatoid arthritis, which contain the JAKinhibitors as defined in 1) as an active ingredient.4) Medicaments containing the compound as defined in any one of 1^(a))to 62^(a)) and 1^(b)) to 44^(b)), tautomers or pharmaceuticallyacceptable salts of the compounds or solvates thereof, as an activeingredient.

The preventive, therapeutic and improving agents for diseases againstwhich inhibition of JAK is effective which contain the JAK inhibitors ofthe present invention, as an active ingredient may usually beadministered as oral medicines such as tablets, capsules, powder,granules, pills and syrup, as rectal medicines, percutaneous medicinesor injections. The agents of the present invention may be administeredas a single therapeutic agent or as a mixture with other therapeuticagents. Though they may be administered as they are, they are usuallyadministered in the form of medical compositions. These pharmaceuticalpreparations can be obtained by adding pharmacologically andpharmaceutically acceptable additives by conventional methods. Namely,for oral medicines, ordinary additives such as excipients, lubricants,binders, disintegrants, humectants, plasticizers and coating agents maybe used. Oral liquid preparations may be in the form of aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs or may be suppliedas dry syrups to be mixed with water or other appropriate solventsbefore use. Such liquid preparations may contain ordinary additives suchas suspending agents, perfumes, diluents and emulsifiers. In the case ofrectal administration, they may be administered as suppositories.Suppositories may use an appropriate substance such as cacao butter,laurin tallow, Macrogol, glycerogelatin, Witepsol, sodium stearate andmixtures thereof as the base and may, if necessary, contain anemulsifier, a suspending agent, a preservative and the like. Forinjections, pharmaceutical ingredients such as distilled water forinjection, physiological saline, 5% glucose solution, propylene glycoland other solvents or solubilizing agents, a pH regulator, anisotonizing agent and a stabilizer may be used to form aqueous dosageforms or dosage forms which need dissolution before use.

The dose of the agents of the present invention for administration tohuman is usually about from 0.1 to 1000 mg/body/day in the case of oraldrugs or rectal administration and about from 0.05 mg to 500 mg/body/dayin the case of injections, though it depends on the age and conditionsof the patient. The above-mentioned ranges are mere examples, and thedose should be determined from the conditions of the patient.

The present invention is used when it is expected to improve pathologyof diseases associated with JAK1, JAK2 and JAK3 separately or incombination. Among these diseases, JAK3-associated diseases are, inaddition to rheumatoid arthristis, inflammatory or proliferativedermatoses such as psoriasis, atopic dermatitis, contact dermatitis,eczematoid dermatitis, seborrheic dermatitis, lichen planus, pemphigus,pemphigoid, epidermolysis bullosa, hives, angioedema, angiitis,erythema, dermal eosinophilia, lupus erythematosus, acne, alopeciaareata, immune dermatoses, reversible airway obstruction, mucitis andangitis. Among these diseases, JAK3- and JAK1-associated diseases are,in addition to rheumatoid arthristis, asthma, atopic dermatitis,Alzheimer disease, atherosclerosis, cancer, leukemia, rejection of organor tissue grafts (such as heart, kidney, liver, bone marrow, skin, horn,lung, pancreas, islet, small intestine, extremities, muscles, nerves,intervertebral disks, trachea, myoblasts and cartilage),graft-versus-host reaction after bone marrow transplantation andautoimmune diseases such as rheumatic disease, systemic lupuserythematosus (SLE), Hashimoto's disease, multiple sclerosis, myastheniagravis, type I diabetes and diabetic complications. Among thesediseases, JAK2-associated diseases include, for example,myeloproliferative disorders.

As an application of the present invention, treatment and prevention ofthe above-mentioned diseases may be mentioned, but there is norestriction.

Compounds of the present invention are administered either alone or incombination with one or more additional agents such as immunomodulators,antiinflammatory agents or antirheumatic drugs. The additional agentsmay be cyclosporin A, tacrolimus, leflunomide, deoxyspergualin,mycophenolate, azathioprine, etanercept (e.g. Enbrer), infliximab (e.g.Remicade), adalimumab (e.g. Humire), certolizumab pegol (e.g. Cimzia®),Golimumab (e.g. Simponi®), Anakinra (e.g. Kineret), rituximab (e.g.Rituxan®), Tocilizumab (e.g. Actemra®), methotrexate, aspirin,acetaminophen, ibuprofen, naproxen, piroxicam, and antiinflmmatorysteroids (e.g. prednisolone or dexamethasone), but are not restrictedthereto.

Now, the present invention will be described in further detail withreference to Reference Synthetic Examples, Synthetic Examples, AssayExamples and Formulation examples. However, it should be understood thatthe present invention is by no means restricted by these specificExamples. In the Examples, “NMR” denotes nuclear magnetic resonance,“LC/MS” denotes high performance liquid chromatography-massspectrometry, “v/v” means volume ratio. In the tables, “Rf” denotesReference Synthetic Example, “Ex” denotes Synthetic Example, “Structure”denotes chemical structural formula, “diastereomixture” denotes adiastereomeric mixture, “racemate” denotes a racemic mixture, “cis/transmixture” denotes a cis- and trans-isomeric mixture, and “E/Z mixture”denotes a E- and Z-isomeric mixture, and “Data” denotes physicalproperty data, “condition” denotes measurement condition, “retentiontime” denotes retention time in LC/MS, “Compound Name” denotes compoundname of the synthesized compound, “Morphology” denotes morphology of asynthesized compound, “Yield” denotes yield of a synthesized compound,“quant” denotes quantitative, “min” denotes minute.

In the Examples herein, “rac-” or “racemate” used in texts or tables fora compound having more than one asymmetric center means that thecompound is in the form of a racemic mixture of the specified absoluteconfiguration and its enantiomer.

The ¹H-NMR data show chemical shifts δ (unit: ppm) (splitting pattern,value of integral) measured at 300 MHz (with JNM-ECP300, manufactured byJEOL Ltd or JNM-ECX300, manufactured by JEOL Ltd) usingtetramethylsilane as an internal standard. “s” denotes “singlet”, “d”denotes “doublet”, “t” denotes “triplet”, “q” denotes “quartet”, “quint”denotes quintet, “sextet” denotes sextet, “septet” denotes septet, “dd”denotes doublet of doublets, “dt” denotes doublet of triplets, “td”denotes triplet of doublets, “dq” denotes doublet of quartets, “qd”denotes quartet of doublets, “tt” denotes triplet of triplets, “ddd”denotes doublet of doublet of doublets, “m” denotes multiplet, “br”denotes broad, “J” denotes coupling constant, “CDCl₃” denotes deuteratedchloroform, “CD₃OD” denotes deuterated methanol, and “DMSO-d₆” denotesdeuterated dimethyl sulfoxide.

For purification by silica gel column chromatography, Hi Flash columnmanufactured by Yamazen Corporation, a silica gel 60 manufactured byMerck & Co., Inc. or PSQ60B manufactured by Fuji Silysia Chemical Ltd.was used unless otherwise noted.

For purification by silica gel thin layer chromatography, PLC platemanufactured by Merck & Co., Inc. was used unless otherwise noted.

As a microwave reactor, Initiator sixty manufactured by Biotage wasused.

LC/MS spectra were measured by using ESI (electrospray ionization).“ESI⁺” denotes ESI-positive mode, and “ESI⁻” denotes ESI-negative mode.

LC/MS condition 1

Instrument: Waters Alliance-ZQ Column: Waters SunFire C18(3.5 μm, 2.1×20mm) Column Temp.: 40° C.

Eluents: Liquid A: 0.1% aqueous formic acid

Liquid B: 0.1% formic acid in acetonitrile

Elution: A mixture of Liquids A and B was flown at 0.4 m L/min while themixing ratio was linearly changed from 90/10 (v/v) to 15/85 (v/v) overthe first 3 minutes, and then the flow rate was linearly changed to 0.5m L/min for 2 minutes at a constant mixing ratio of 15/85 (v/v). Then,the mixing ratio was linearly changed to 90/10 (v/v) over 0.5 minute andmaintained at 90/10 (v/v) for 2.5 minutes.LC/MS condition 2

Instrument: Waters Alliance-ZQ Column: Waters SunFire C18(3.5 μm, 2.1×20mm) Column Temp.: 40° C.

Eluents: Liquid A: 0.2% aqueous formic acid

Liquid B: acetonitrile

Elution: A mixture of Liquids A and B was flown at 0.4 mL/min while themixing ratio was linearly changed from 90/10 (v/v) to 15/85 (v/v) overthe first 3 minutes, and then the flow rate was linearly changed to 0.5m L/min over 2 minutes at a constant mixing ratio of 15/85 (v/v). Then,the mixing ratio was linearly changed to 95/5 (v/v) over 0.5 minute andmaintained at 95/5 (v/v) for 1.5 minutes.LC/MS condition 3

Instrument: Thermo LTQ XL Column: Waters AQUITY UPLC BEH C18(1.7 μm,2.1×50 mm) Column Temp.: 40° C.

Eluents: Liquid A: 0.1% aqueous formic acid

Liquid B: 0.1% formic acid in acetonitrile

Elution: A mixture of Liquids A and B was flown at 0.6 mL/min at amixing ratio of 90/10 (v/v) for the first 0.5 minutes, and then themixing ratio was linearly changed to 10/90 (v/v) over 2.5 minutes andthen maintained at 10/90 (v/v) for 0.7 minute. The mixing ratio and theflow rate were linearly changed to 90/10 (v/v) and 0.8 mL/min,respectively, over 0.1 minute, maintained constant for 1 minute andlinearly changed to 90/10 (v/v) and 0.6 mL/min, respectively, over 0.1minute.

Reference Synthetic Example^(a) 1 4-lodo-7H-pyrrolo[2,3-d]pyrimidine

Hydroiodic acid (55 wt %, 100 g) was mixed with4-chloro-7H-pyrrolo[2,3-d]pyrimidine (manufactured by Tokyo ChemicalIndustry Co., Ltd., 10.6 g, 69.0 mmol) under cooling with ice andstirred at 0° C. for 1 hour and then at room temperature for one day.The precipitated solid was collected by filtration and washed withwater. The residue was suspended in water, neutralized with 1 M aqueoussodium hydroxide and filtered. The yellow solid was washed with waterand dried under reduced pressure to give the title compound as a yellowsolid (16.2 g, yield 96%, including 10%4-chloro-7H-pyrrolo[2,3-d]pyrimidine as the starting compound).

Reference Synthetic Example^(a) 24-lodo-7-(triisopropylsilyl)-7H-pyrrolo[2,3-d]pyrimidine

4-lodo-7H-pyrrolo[2,3-d]pyrimidine (352 mg, 1.44 mmol) intetrahydrofuran (15 mL) cooled to 0° C. was mixed with sodium hydride(55 wt % dispersion in mineral oil, 75.5 mg, 1.73 mmol) andchlorotriisopropylsilane (0.37 mL, 1.7 mmol) and stirred at roomtemperature for 45 minutes. After addition of water, the reactionmixture was extracted with ethyl acetate, and the organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate=100/1 (v/v)) to give the title compound as a paleyellow oil (431 mg, yield 74%).

Reference Synthetic Example^(a) 3Cyclohexyl[7-(triisopropylsilyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]methanol

n-Butyllithium (1.6 M solution in hexane, 0.23 mL, 0.380 mmol) wasgradually added dropwise to4-iodo-7-(triisopropylsilyl)-7H-pyrrolo[2,3-d]pyrimidine (126 mg, 0.310mmol) in tetrahydrofuran (1.5 mL) cooled to −78° C., and the reactionmixture was stirred at −78° C. for 30 minutes. After addition ofcyclohexanecarbaldehyde (42 μL, 0.35 mmol) in tetrahydrofuran (1.5 mL),the reaction mixture was gradually warmed from −78° C. to roomtemperature and stirred for one day. After addition of saturated aqueousammonium chloride, the reaction mixture was extracted with ethylacetate, and the organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (Hi Flash column amino typemanufactured by Yamazen Corporation: hexane/ethyl acetate=10/1→7/1→4/1(v/v)) to give the title compound as a colorless oil (65.5 mg, yield55%).

Reference Synthetic Example^(a) 4Cyclohexyl[7-(triisopropylsilyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]methanone

Cyclohexyl[7-(triisopropylsilyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]methanol(211 mg, 0.540 mmol) in dichloromethane (7 mL) was stirred with1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (347 mg, 0.820mmol) at room temperature for 2.5 hours. After addition of a mixture(1/1 (v/v)) of saturated aqueous sodium hydrogen carbonate and saturatedaqueous sodium thiosulfate, the reaction mixture was extracted withethyl acetate, and the organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate=30/1(v/v)) to give the title compound as a colorless solid (117 mg, yield55%).

Reference Synthetic Example^(a) 5Cyclohexyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone

Cyclohexyl[7-(triisopropylsilyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]methanone(22.4 mg, 58.0 μmol) was stirred with hydrogen chloride-methanolsolution (10 wt %, 2.0 mL) at room temperature for 15 minutes. Thereaction mixture was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (Hi Flashcolumn amino type manufactured by Yamazen Corporation:chloroform/methanol=10/1 (v/v)) to give the title compound as a paleyellow oil (9.2 mg, yield 69%).

Reference Synthetic Example^(a) 6Cyclohexyl(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone

Cyclohexyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone (50.0 mg, 0.218mmol) in N,N-dimethylformamide (1 mL) was mixed with sodium hydride (60wt % dispersion in mineral oil, 9.6 mg, 0.24 mmol) and[2-(chloromethoxy)ethyl]trimethylsilane (42.5 μL, 0.240 mmol) undercooling with ice and stirred for 30 minutes while the temperature wasgradually raised to room temperature. Separately,cyclohexyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone (500 mg, 2.18 mmol)in N,N-dimethylformamide (5 mL) was mixed with sodium hydride (60 wt %dispersion in mineral oil, 96 mg, 2.4 mmol) and(chloromethoxy)ethyl]trimethylsilane (425 μL, 2.40 mmol) under coolingwith ice and stirred for 30 minutes while the temperature was graduallyraised to room temperature. After addition of water, the reactionsolution and the previously obtained reaction solution were extractedwith ethyl acetate, respectively, and the organic layers were washedwith saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The resulting residueswere combined and purified by silica gel column chromatography(hexane/ethyl acetate=5/1 (v/v)) to give the title compound as a paleyellow oil (850 mg, yield 99%).

Reference Synthetic Example^(a) 7Cyclohexyl(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanamine

Cyclohexyl(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone(406 mg, 1.13 mmol) in methanol (10 ml) was stirred with hydroxylaminehydrochloride (395 mg, 5.66 mmol) for 4 hours. After addition of water,the reaction mixture was extracted with ethyl acetate, and the organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure. The resulting residue was dissolved in ethanol (3.0mL), mixed with ammonium acetate (105 mg, 1.36 mmol), water (3 mL) andaqueous ammonia (5 mL) and refluxed with zinc powder (600 mg, 9.17 mmol)for 4 hours. The reaction mixture was allowed to cool to roomtemperature and filtered, and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (Hi Flash column amino type manufactured by YamazenCorporation: chloroform/methanol=20/1 (v/v)) to give the title compoundas a yellow oil (390 mg, yield 79%).

Reference Synthetic Example^(a) 81-Cyclohexyl-7{[2-(trimethylsilyl)ethoxy]methyl}-7H-imidazo[1,5-c]pyrrolo[3,2-e]pyrimidine

Cyclohexyl(7-{[2-(trimethylsilyl)ehoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanamine(10 mg. 0.028 mmol) in N,N-dimethylformamide dimethyl acetal (0.7 mL)was stirred at 170° C. for 30 minutes under microwave irradiation. Thereaction mixture was allowed to cool to room temperature andconcentrated under reduced pressure, and the resulting residue wasdissolved in 1,3-dimethylimidazolidin-2-one (1.0 mL) and stirred at 230°C. for 1.5 hours under microwave irradiation. Separately,cyclohexyl(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-ylmethanamine(89 mg, 0.25 mmol) in N,N-dimethylformamide dimethyl acetal (1 mL) wasstirred at 170° C. for 30 minutes under microwave irradiation. Thereaction mixture was allowed to cool to room temperature andconcentrated under reduced pressure, and the resulting residue wasdissolved in 1,3-dimethylimidazolidin-2-one (4.5 mL) and stirred at 230°C. for 1.5 hours under microwave irradiation. The reaction mixture andthe previously obtained reaction mixture were combined, diluted withethyl acetate, acidified with 1 M hydrochloric acid and washed withsaturated aqueous ammonium chloride and saturated aqueous sodiumchloride, and the organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel thin layer chromatography (hexane/ethyl acetate=2/1→1/1→1/2(v/v)) to give the title compound as a pale yellow oil (31.4 mg, yield30%).

Reference Synthetic Example^(a) 9 N-Methoxy-N,2-dimethylbenzamide

2-Methylbenzoic acid (1.00 g, 7.34 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.69 g,8.81 mmol) in chloroform (10 mL) stirred with N,N-diisopropylethylamine(1.50 mL, 8.81 mmol) for 10 minutes under cooling with ice and thenstirred with N,O-dimethylhydroxylamine hydrochloride (860 mg, 8.81 mmol)and N,N-diisopropylethylamine (1.50 mL, 8.81 mmol) for one day while thetemperature was gradually raised to room temperature. After addition ofwater, the reaction mixture was extracted with chloroform, and theorganic layer was washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate=1/1 (v/v)) to give the title compound as a paleyellow oil (658 mg, yield 50%).

Reference Synthetic Example^(a) 10(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)(o-tolyl)methanone

Isopropylmagnesium chloride (2.0 M solution in tetrahydrofuran, 1.05 mL,2.10 mmol) was gradually added dropwise to4-iodo-7H-pyrrolo[2,3-d]pyrimidine (245 mg, 1.00 mmol) obtained inReference Synthetic Example^(a) 1 in tetrahydrofuran (5 mL) cooled to−78° C., and the resulting reaction mixture was stirred at −78° C. for15 minutes. The reaction mixture was warmed to room temperature andstirred with (2,6-dimethylphenyl)magnesium bromide (1.0 M solution intetrahydrofuran, 1.1 mL, 1.1 mmol) and N-methoxy-N,2-dimethylbenzamide(180 mg, 1.00 mmol) in tetrahydrofuran (4 mL) at room temperature forone day. After addition of saturated aqueous ammonium chloride, thereaction mixture was extracted with ethyl acetate, and the organic layerwas washed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (hexane/ethylacetate=2/1→>1/1 (v/v)) to give the title compound as a pale yellowsolid (162 mg, yield 68%).

Reference Synthetic Example′ 11 N-Methoxy-N-methylcyclohexanecarboxamide

The reactions in Reference Synthetic Example^(a) 9 were carried out insubstantially the same manners except that cyclohexanecarboxylic acidwas used instead of 2-methylbenzoic acid to give the title compound as acolorless oil (2.14 g, yield 46%).

Reference Synthetic Example^(a) 12Cyclohexyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone

The reactions in Reference Synthetic Example^(a) 10 were carried out insubstantially the same manners except thatN-methoxy-N-methylcyclohexanecarboxamide was used instead ofN-methoxy-N,2-dimethylbenzamide to give the title compound as a paleyellow solid (1.26 g, yield 67%).

Reference Synthetic Example^(a) 13N-Methoxy-N,2-dimethylcyclohexanecarboxamide

The reactions in Reference Synthetic Example^(a) 9 were carried out insubstantially the same manners except that 2-methylcyclohexanecarboxylicacid was used instead of 2-methylbenzoic acid to give the title compoundas a colorless oil (623 mg, yield 48%).

Reference Synthetic Example^(a) 14(2-Methylcyclohexyl)(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone

The reactions in Reference Synthetic Example^(a) 10 were carried out insubstantially the same manners except thatN-methoxy-N,2-dimethylcyclohexanecarboxamide was used instead ofN-methoxy-N,2-dimethylbenzamide to give the title compound as acolorless solid (165 mg, yield 68%).

Reference Synthetic Example^(a) 154-lodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

4-lodo-7H-pyrrolo[2,3-d]pyrimidine (90 mg, 0.037 mmol) obtained inReference Synthetic Example^(a) 1 in N,N-dimethylformamide (4 mL) wasstirred with sodium hydride (55 wt % dispersion in mineral oil, 19.2 mg,0.0440 mmol) and [2-(chloromethoxy)ethyl]trimethylsilane (77.9 μL,0.0440 mmol) at room temperature for one day. After addition ofsaturated aqueous sodium chloride, the reaction mixture was extractedwith ethyl acetate, and the organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=10/1→4/1 (v/v)) to give the title compound as a colorless oil(115 mg, yield 83%).

Reference Synthetic Example^(a) 16 Benzyl3-(hydroxymethyl)piperidine-1-carboxylate

3-Piperidinemethanol (3.59 g, 31.2 mmol) in 1,4-dioxane (8 mL) was mixedwith potassium carbonate (4.55 g, 33.0 mmol), 1 M aqueous sodiumhydroxide (2 mL) and benzyl chloroformate (5.20 mL, 36.4 mmol) undercooling with ice and stirred at room temperature for one day. Afteraddition of water, the reaction mixture was extracted with ethylacetate, and the organic layer was washed with saturated aqueouspotassium hydrogen sulfate and saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (hexane/ethyl acetate=1/1 (v/v)) to give the titlecompound as a colorless oil (6.41 g, yield 83%).

Reference Synthetic Example^(a) 17 Benzyl3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate

Benzyl 3-(hydroxymethyl)piperidine-1-carboxylate (2.0 g, 8.0 mmol) indichloromethane (50 mL) was stirred with1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (5.1 g, 12 mmol)at room temperature for 2.5 hours. After addition of a mixture(1/1(v/v)) of saturated aqueous sodium hydrogen carbonate and saturatedaqueous sodium thiosulfate, the reaction mixture was extracted withethyl acetate, and the organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The resulting residuewas dissolved in t-butanol (25 mL), mixed with sodium dihydrogenphosphate (2.89 g, 24.1 mmol), water (25 mL) and 2-methyl-2-butene (25mL, 241 mmol), then stirred with sodium chlorite (3.62 g, 40.1 mmol) at0° C. for 1 hour and then stirred at room temperature for 1 hour. Afteraddition of saturated aqueous sodium thiosulfate, the reaction mixturewas extracted with ethyl acetate, and the organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresulting residue was dissolved in N,N-dimethylformamide (60 mL) andmixed with N,O-dimethylhydroxylamine hydrochloride (1.02 g, 10.4 mmol)and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (4.0 g, 10.4 mmol) and then stirred withtriethylamine (1.5 mL, 10 mmol) at room temperature for 2.5 hours. Afteraddition of water, the reaction mixture was extracted with ethylacetate, and the organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=3/1→1/1 (v/v)) togive the title compound as a pale yellow oil (1.44 mg, yield 59% (threesteps)).

Reference Synthetic Example^(a) 18 Benzyl3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)piperidine-1-carboxylate

Isopropylmagnesium chloride (2.0 M solution in tetrahydrofuran, 0.4 mL,0.80 mmol) was gradually added dropwise to4-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine(200 mg, 0.530 mmol) obtained in Reference Synthetic Example^(a) 15 intetrahydrofuran (3 mL) cooled to −78° C., and the resulting reactionmixture was stirred at −78° C. for 15 minutes. The reaction mixture waswarmed to room temperature and stirred with(2,6-dimethylphenyl)magnesium bromide (1.0 M solution intetrahydrofuran, 0.8 mL, 0.80 mmol) and benzyl3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (245 mg, 0.800mmol) in tetrahydrofuran (3.0 mL) at room temperature for 2.5 hours.After addition of saturated aqueous ammonium chloride, the reactionmixture was extracted with ethyl acetate, and the organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate=4/1→2/1→1/1 (v/v)) to give the title compound as ayellow oil (107 mg, yield 41%).

Reference Synthetic Example^(a) 19 Benzyl3-[amino(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl]piperidine-1-carboxylate

The reactions in Reference Synthetic Example^(a) 7 were carried out insubstantially the same manners except that3-(7-{[2-(trimethylsilyl)ehoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)piperidine-1-carboxylate(253 mg, 0.510 mmol) was used instead ofcyclohexyl(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanoneto give the title compound as a pale blue oil (183 mg, yield 72%).

Reference Synthetic Example^(a) 20 Benzyl3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-imidazo[1,5-c]pyrrolo[3,2-e]pyrimidin-1-yl)piperidine-1-carboxylate

Benzyl3-[amino(7-{[2-(trimethylsilyl)ethoxy]methy}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl]piperidine-1-carboxylate(63 mg, 0.13 mmol) in N,N-dimethylformamide dimethyl acetal (1 mL) wasstirred at 170° C. for 30 minutes under microwave irradiation. Thereaction mixture was allowed to cool to room temperature andconcentrated under reduced pressure, and the resulting residue wasdissolved in 1,3-dimethylimidazolidin-2-one (1 mL) and stirred at 230°C. for 1.5 hours under microwave irradiation. The reaction mixture wasallowed to cool to room temperature, diluted with ethyl acetate andwashed with saturated aqueous ammonium chloride and saturated aqueoussodium chloride, and the organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The concentrate waspurified by silica gel thin layer chromatography (hexane/ethylacetate=1/1→1/2 (v/v)) to give a brown oil containing the title compound(45.2 mg). The resulting mixture was used for the next step.

Reference Synthetic Example^(a) 21trans-4-(Hydroxymethyl)-N-methoxy-N-methylcyclohexanecarboxamide

The reactions in Reference Synthetic Example^(a) 9 were carried out insubstantially the same manners except thattrans-4-(hydroxylmethyl)cyclohexanecarboxylic acid (manufactured byTokyo Chemical Industry Co., Ltd.) was used instead of 2-methylbenzoicacid to give the title compound as a colorless oil (515 mg, yield 41%).

Reference Synthetic Example^(a) 22trans-4-[(tert-Butyldiphenylsilyloxy)methyl]-N-methoxy-N-methylcyclohexanecarboxamide

trans-4-(Hydroxymethyl)-N-methoxy-N-methylcyclohexanecarboxamide (403mg, 2.00 mmol) in N,N-dimethylformamide (4 mL) was mixed withtert-butylchlorodiphenylsilane (514 μL, 2.00 mmol) and 1H-imidazole (136mg, 2.00 mmol) under cooling with ice and stirred for one day while thetemperature was gradually raised to room temperature. After addition ofwater, the reaction mixture was extracted with ethyl acetate, and theorganic layer was washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate=8/1 (v/v)) to give the title compound as acolorless oil (536 mg, yield 61%).

Reference Synthetic Example^(a) 23{trans-4-[(tert-Butyldiphenylsilyloxy)methyl]cyclohexyl}(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone

The reactions in Reference Synthetic Example^(a) 10 were carried out insubstantially the same manners except thattrans-4-[(tert-butyldiphenylsilyloxy)methyl]-N-methoxy-N-methylcyclohexanecarboxamidewas used instead of N-methoxy-N,2-dimethylbenzamide to give the titlecompound as a yellow oil (111 mg, yield 59%).

Reference Synthetic Example^(a) 241-{trans-4-[(tert-Butyldiphenylsilyloxy)methyl]cyclohexyl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

The reactions in Synthetic Example^(a) 5 were carried out insubstantially the same manners except that{trans-4-[(tert-butyldiphenylsilyloxy)methyl]cyclohexyl}(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanoneobtained in Reference Synthetic Example^(a) 23 was used instead of(7H-pyrrolo[2,3-d]pyrimidin-4-yl)(o-tolyl)methanone to give the titlecompound as a pale yellow solid (50.6 mg, yield 46%).

Reference Synthetic Example^(a) 25 3-Methyl 1-tert-butyl4-methylpiperidine-1,3-dicarboxylate

4-Methylpyridine-3-carboxylic acid (1.13 g, 6.48 mmol) in methanol (20mL) was refluxed with concentrated sulfuric acid (4.0 mL) for 2 daysunder heating. The reaction mixture was concentrated under reducedpressure, gradually adjusted to pH 8 or above with saturated aqueoussodium hydrogen carbonate and extracted with ethyl acetate twice. Theresulting organic layer was washed with water and saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure to give a red oil (0.89 g). The reactions werecarried out with 4-methylpyridine-3-carboxylic acid (1.77 g, 10.2 mmol)to give a red oil (1.37 g).

The red oil (2.26 g) obtained above was dissolved in ethyl acetate (35mL) was stirred with active carbon (400 mg) at room temperature for 30minutes. The mixture was filtered, and the filtrate was concentratedunder reduced pressure. The resulting residue was dissolved in aceticacid (35 mL) and stirred with platinum(IV) oxide (162 mg) under ahydrogen atmosphere at 0.5 MPa for 3 days. The reaction mixture wasfiltered, and the filtrate was concentrated under reduced pressure. Theresulting residue was dissolved in acetonitrile (50 mL) and water (40mL) and stirred with sodium hydrogen carbonate (5.00 g, 59.5 mmol) andtert-butyl bicarbonate (5.10 g, 23.4 mmol) for one day. The reactionmixture was extracted with diethyl ether twice, and the organic layerwas washed with 1 M hydrochloric acid and saturated aqueous magnesiumchloride, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the titlecompound as a colorless oil (4.33 g, yield 90% (three steps)).

Reference Synthetic Example^(a) 26 tert-Butyl3-[methoxy(methyl)carbamoyl]-4-methylpiperidine-1-carboxylate

Diisobutylaluminum hydride (1.0 M solution in toluene, 23.4 mL, 23.7mmol) was added dropwise to 3-methyl 1-tert-butyl4-methylpiperidine-1,3-dicarboxylate (2.43 g, 9.46 mmol) intetrahydrofuran (60 mL) cooled to −78° C., and the resulting reactionmixture was stirred at −78° C. for 1 hour and at room temperature for 2hours, then stirred with methanol and Celite at room temperature for 30minutes and filtered. The filtrate was concentrated under reducedpressure. The resulting residue was roughly purified by silica gelcolumn chromatography (hexane/ethyl acetate=4/1→2/1→1/1 (v/v)) to give acolorless oil (1.62 g). The crude product (1.02 g) was dissolved indichloromethane (30 m L) and stirred with1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (2.83 g, 6.67mmol) at room temperature for 1.5 hours. After addition of a mixture(1/1 (v/v)) of saturated aqueous sodium hydrogen carbonate and saturatedaqueous sodium thiosulfate, the reaction mixture was extracted withethyl acetate, and the organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The resulting residuewas dissolved in t-butanol (12 mL), mixed with sodium dihydrogenphosphate (1.33 g, 11.1 mmol), water (12 mL) and 2-methyl-2-butene (12mL, 111 mmol) and stirred with sodium chlorite (1.68 g, 18.6 mmol) undercooling with ice for 30 minutes and then at room temperature 1 hour.After addition of saturated aqueous sodium thiosulfate, the reactionmixture was extracted with ethyl acetate, and the organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure. The resulting residue was dissolved in N,N-dimethylformamide(30 mL), mixed with N,O-dimethylhydroxylamine hydrochloride (396 mg,4.06 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (2.00 g, 5.41 mmol) and stirred withN,N-diisopropylethylamine (1.50 mL, 8.45 mmol) at room temperature forone day. After addition of water, the reaction solution was extractedwith ethyl acetate, and the organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=4/1→2/1 (v/v)) to give the title compound as a pale yellow oil(644 mg, yield 38% (four steps)).

Reference Synthetic Example^(a) 27 tert-Butyl4-methyl-3-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)piperidine-1-carboxylate

The reactions in Reference Synthetic Example^(a) 10 were carried out insubstantially the same manners except that tert-butyl3-[methoxy(methyl)carbamoyl]-4-methylpiperidine-1-carboxylate was usedinstead of N-methoxy-N,2-dimethylbenzamide to give the title compound asa pale yellow solid (53.8 mg, yield 73%).

Reference Synthetic Example^(a) 28 tert-Butyl3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate

The reactions in Reference Synthetic Example^(a) 9 were carried out insubstantially the same manners except that1-(tert-butoxycarbonyl)piperidine-3-carboxylate was used instead of2-methylbenzoic acid to give the title compound as a colorless oil (1.68g, yield 57%).

Reference Synthetic Example^(a) 29 tert-Butyl3-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)piperidine-1-carboxylate

The reactions in Reference Synthetic Example^(a) 10 were carried out insubstantially the same manners except that tert-butyl3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate was used instead ofN-methoxy-N,2-dimethylbenzamide to give the title compound as a paleyellow solid (1.19 g, yield 68%).

Reference Synthetic Example^(a) 301-[(Benzyloxy)carbonyl]piperidine-3-carboxylic acid

Nipecotic acid (3.93 g, 30.4 mmol) and sodium carbonate (5.10 g, 48.1mmol) in water (40 mL) was mixed with benzyl chloroformate (5.20 mL,36.4 mmol) under cooling with ice and stirred at room temperature forone day. After addition of water and 1 M aqueous sodium hydroxide, thereaction mixture was allowed to separate by adding diethyl ether. Theaqueous layer was adjusted to pH 1 with concentrated hydrochloric acidand extracted with ethyl acetate. The resulting organic layer was washedwith saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to give the titlecompound as a pale yellow oil (5.86 g, yield 73%).

Reference Synthetic Example^(a) 31 Benzyl3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate

1-[(Benzyloxy)carbonyl]piperidine-3-carboxylic acid (5.86 g, 22.3 mmol)and N,O-dimethylhydroxylamine hydrochloride (3.55 g, 36.4 mmol) intetrahydrofuran (60 mL) was stirred with triethylamine (5.50 mL, 39.5mmol), 1-hydroxybenzotriazole (1.17 g, 8.66 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.18 g,37.4 mmol) at room temperature for one day. After addition of water, thereaction solution was extracted with ethyl acetate, and the organiclayer was washed with saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=1/1 (v/v)) to give the title compound as a colorless oil (5.95g, yield 87%).

Reference Synthetic Example^(a) 32 Benzyl3-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)piperidine-1-carboxylate

The reactions in Reference Synthetic Example^(a) 10 were carried out insubstantially the same manners except that benzyl3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate was used instead ofN-methoxy-N,2-dimethylbenzamide to give the title compound as a paleyellow solid (3.56 g, yield 53%)_(.)

Reference Synthetic Example^(a) 33 1-Benzylpiperidine-3-carboxylic acid

Nipecotic acid (1.31 g, 10.2 mmol), benzaldehyde (1.12 g, 10.6 mmol) and5% palladium-carbon (0.18 g) in methanol (10 mL) was stirred at roomtemperature for one day under a hydrogen atmosphere. The reactionmixture was filtered, and the filtrate was concentrated under reducedpressure. The resulting residue was dissolved in methanol (50 mL) wasstirred with benzaldehyde (4.40 g, 41.5 mmol) and 5% palladium-carbon(0.118 g) at room temperature for one day. The reaction mixture wasfiltered, and the filtrated was concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(chloroform/methanol=10/1→5/1 (v/v)) to give the title compound as acolorless oil (1.41 g, yield 63%).

Reference Synthetic Example^(a) 341-Benzyl-N-methoxy-N-methylpiperidine-3-carboxamide

1-Benzylpiperidine-3-carboxylic acid (318 mg, 1.45 mmol) andN,O-dimethylhydroxylamine hydrochloride (287 mg, 2.94 mmol) intetrahydrofuran (5 mL) was stirred with triethylamine (283 μL, 2.03mmol), 1-hydroxybenzotriazole (101 mg, 0.747 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (560 mg,2.92 mmol) at room temperature for one day. After addition of water, thereaction mixture was extracted with ethyl acetate, and the organic layerwas washed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residueswas purified by silica gel column chromatography (hexane/ethylacetate=1/1 (v/v)) to give the title compound as a colorless oil (272mg, yield 71%).

Reference Synthetic Example^(a) 35(1-Benzylpiperidin-3-yl)(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone

The reactions in Reference Synthetic Example^(a) 10 were carried out insubstantially the same manners except that1-benzyl-N-methoxy-N-methylpiperidine-3-carboxamide was used instead ofN-methoxy-N,2-dimethylbenzamide to give the title compound as a yellowamorphous (121 mg, yield 91%).

Reference Synthetic Example^(a) 36 Phenyl 1,3,4-thiadiazol-2-ylcarbamate

1,3,4-Thiadiazol-2-amine (253 mg, 2.50 mmol) in dimethylacetamide (3 mL)was stirred with phenyl chloroformate (392 μL, 3.13. mmol) at roomtemperature for one day. After addition of water, the precipitated solidwas collected by filtration, washed with water and hexane and driedunder reduced pressure to give the title compound as a colorless solid(418 mg, yield 76%).

Reference Synthetic Example^(a) 37Phenyl(3-methylisothiazol-5-yl)carbamate

3-Methythiazol-5-amine (156 mg, 1.04 mmol) in pyridine (1.2 mL) wasmixed with phenyl chloroformate (260 μL, 2.07 mmol) under cooling withice and stirred at room temperature for 3 hours. The reaction mixturewas concentrated under reduced pressure, and after addition of water,extracted with chloroform twice, and the organic layer was concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the titlecompound as a pale yellow solid (173 mg, yield 71%).

Reference Synthetic Example^(a) 38 tert-Butyl4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate

The reactions in Reference Synthetic Example^(a) 9 were carried out insubstantially the same manners except that1-(tert-butoxycarbonyl)piperidine-carboxylic acid was used instead of2-methylbenzoic acid to give the title compound as a colorless oil (763mg, yield 64%).

Reference Synthetic Example^(a) 39 tert-Butyl4-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)piperidine-1-carboxylate

The reactions in Reference Synthetic Example^(a) 10 were carried out insubstantially the same manners except that tert-butyl4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate was used instead ofN-methoxy-N,2-dimethylbenzamide to give the title compound as a paleyellow amorphous (486 mg, yield 74%).

Reference Synthetic Example^(a) 40N-Methoxy-N-methylpiperidine-4-carboxamide hydrochloride

tert-Butyl 4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (1.00 g,3.67 mmol) obtained in Reference Synthetic Example^(a) 38 in 1,4-dioxane(10 mL) was stirred with 4 M hydrogen chloride-1,4-dioxane solution (8mL) at room temperature for one day. The solid precipitated in thereaction mixture was collected by filtration to give the title compoundas a colorless solid (650 mg, yield 85%).

Reference Synthetic Example^(a) 41N-Methoxy-N-methyl-1-(2,2,2-trifluoroethyl)piperidine-4-carboxamide

N-Methoxy-N-methylpiperidine-4-carboxamide hydrochloride (600 mg, 2.88mmol) in water (5 mL) was adjusted to pH 10 with 1 M aqueous sodiumhydroxide and extracted with 1-butanol. The organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure to givea colorless solid. The resulting solid (200 mg, 1.16 mmol) was dissolvedin N,N-dimethylformamide (4 mL) and stirred with potassium carbonate(481 mg, 3.48 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate(335 μL, 2.32 mmol) at room temperature for one day. After addition ofwater and saturated aqueous sodium chloride, the reaction mixture wasextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography(methanol/chloroform=1/19→1/9 (v/v)) to give the title compound as acolorless oil (190 mg, yield 26%).

Reference Synthetic Example^(a) 42(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)[1-(2,2,2-trifluoroethyl)piperidin-4-yl]methanone

The reactions in Reference Synthetic Example^(a) 10 were carried out insubstantially the same manners except thatN-methoxy-N-methyl-1-(2,2,2-trifluoroethyl)piperidine-4-carboxamide wasused instead of N-methoxy-N,2-dimethylbenzamide to give the titlecompound as a colorless solid (100 mg, yield 43%).

Reference Synthetic Example^(a) 43 Benzyl4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate

Benzyl chloroformate (1.64 mL, 11.6 mmol) was gradually added dropwiseto piperidine-4-carboxylic acid (1.00 g, 7.74 mmol) and sodium carbonate(1.64 g, 15.5 mmol) in water (20 mL) under cooling with ice, and theresulting reaction mixture was stirred for 2 hours. After addition of 1M aqueous sodium hydroxide, the reaction mixture was allowed to separateby adding ethyl acetate. The resulting aqueous layer was adjusted to pH4 with 1 M hydrochloric acid and extracted with ethyl acetate, and theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure to give a colorless oil. The oil was dissolved inchloroform (30 mL) and stirred with N,O-dimethylhydroxylaminehydrochloride (1.50 g, 15.4 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.00 g,15.4 mmol), 1-hydroxybenzotriazole (2.00 g, 15.4 mmol) and triethylamine(3.2 mL, 23.1 mmol) at room temperature for 3 days. After addition ofwater and saturated aqueous ammonium chloride, the reaction mixture wasextracted with chloroform, and the organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=1/1 (v/v)) to give the title compound as a colorless oil (1.57g, yield 66%).

Reference Synthetic Example^(a) 44 Benzyl4-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)piperidine-1-carboxylate

The reactions in Reference Synthetic Example^(a) 10 were carried out insubstantially the same manners except that benzyl4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate was used instead ofN-methoxy-N,2-dimethylbenzamide to give the title compound as a yellowoil (1.40 g, yield 78%).

Reference Synthetic Example^(a) 45 tert-Butyl{trans-4-[methoxy(methyl)carbamoyl]cyclohexyl}carbamate

trans-4-Aminocyclohexanecarboxylic acid (500 mg, 3.49 mmol) in water (10mL) was stirred with di-tert-butyl bicarbonate (1.50 g, 6.98 mmol) andsodium hydroxide (280 mg, 6.98 mmol) at room temperature for 2 hours.The reaction mixture was washed with ethyl acetate, and the aqueouslayer was adjusted to pH 3 with 1 M hydrochloric acid and extracted withethyl acetate. The organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure to give a colorless oil. The oilwas dissolved in chloroform (10 mL) and stirred withN,O-dimethylhydroxylamine hydrochloride (683 mg, 7.00 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.34 g,7.00 mmol), 1-hydroxybenzotriazole (946 mg, 7.00 mmol) and triethylamine(1.50 mL, 10.5 mmol) at room temperature for one day. After addition ofwater and saturated aqueous sodium chloride, the reaction mixture wasextracted with chloroform, and the organic layer was dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=2/1→1/1 (v/v)) to give the title compound as a colorless solid(513 mg, yield 51%).

Reference Synthetic Example^(a) 46 tert-Butyl[trans-4-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)cyclohexyl]carbamate

The reactions in Reference Synthetic Example^(a) 10 were carried out insubstantially the same manners except that tert-butyl{trans-4-[methoxy(methyl)carbamoyl]cyclohexyl}carbamate was used insteadof N-methoxy-N,2-dimethylbenzamide to give the title compound as acolorless solid (52.0 mg, yield 8.4%).

Reference Synthetic Example^(a) 47Benzyl{trans-4-[methoxy(methyl)carbamoyl]cyclohexyl}carbamate

Benzyl chloroformate (885 μL, 6.30 mmol) was gradually added dropwise totrans-4-aminocyclohexanecarboxylic acid (600 mg, 4.20 mmol) and sodiumcarbonate (891 mg, 8.40 mmol) in water (12 mL) under cooling with ice,and the reaction mixture was stirred for one day. After addition of 1 Maqueous sodium hydroxide and ethyl acetate, the insoluble solid wascollected by filtration to give a colorless solid. The solid wasdissolved in chloroform (10 mL) and stirred withN,O-dimethylhydroxylamine hydrochloride (416 mg, 4.27 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (819 mg,4.27 mmol), 1-hydroxybenzotriazole (577 mg, 4.27 mmol) and triethylamine(892 μL, 6.40 mmol) at room temperature for one day. After addition ofwater and saturated aqueous sodium chloride, the reaction mixture wasextracted with chloroform, and the organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(hexane/ethyl acetate=2/1 (v/v)) to give the title compound as acolorless solid (350 mg, yield 26%).

Reference Synthetic Example^(a) 48Benzyl[trans-4-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)cyclohexyl]carbamate

The reactions in Reference Synthetic Example^(a) 10 were carried out insubstantially the same manners except that benzyl{trans-4-[methoxy(methyl)carbamoyl]cyclohexyl}carbamate was used insteadof N-methoxy-N,2-dimethylbenzamide to give the title compound as acolorless solid (33.0 mg, yield 9.0%).

Reference Synthetic Example^(a) 49trans-N-Methoxy-4-(methoxymethyl)-N-methylcyclohexanecarboxamide

trans-4-(Hydroxymethyl)-N-methoxy-N-methylcyclohexanecarboxamide (200mg, 0.994 mmol) obtained in Reference Synthetic Example^(a) 21 inN,N-dimethylformamide (2 mL) was mixed with sodium hydride (55 wt %dispersion in mineral oil, 52.0 mg, 1.19 mmol) and methyl iodide (74.0μL, 1.19 mmol) under cooling with ice and stirred for 1 hour while thetemperature was gradually raised to room temperature. After addition ofwater, the reaction mixture was extracted with ethyl acetate, and theorganic layer was washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane=1/2→1/1 (v/v)) to give the title compound as acolorless oil (197 mg, yield 92%).

Reference Synthetic Example^(a) 50[trans-4-(Methoxymethyl)cyclohexyl](7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone

The reactions in Reference Synthetic Example^(a) 10 were carried out insubstantially the same manners except thattrans-N-methoxy-4-(methoxymethyl)-N-methylcyclohexanecarboxamide wasused instead of N-methoxy-N,2-dimethylbenzamide to give the titlecompound as an ivory solid (153 mg, yield 70%).

Reference Synthetic Example^(a) 51trans-4-Hydroxy-N-methoxy-N-methylcyclohexanecarboxamide

The reactions in Reference Synthetic Example^(a) 9 were carried out insubstantially the same manners except thattrans-4-hydroxycyclohexanecarboxylic acid was used instead of2-methylbenzoic acid to give the title compound as a colorless oil (1.89g, yield 48%).

Reference Synthetic Example^(a) 52trans-N,4-Dimethoxy-N-methylcyclohexanecarboxamide

trans-4-Hydroxy-N-methoxy-N-methylcyclohexanecarboxamide (536 mg, 2.86mmol) in N,N-dimethylformamide (5 mL) was mixed with sodium hydride (55wt % dispersion in mineral oil, 150 mg, 3.44 mmol) and methyl iodide(214 μL, 3.44 mmol) under cooling with ice and stirred for 3 hours whilethe temperature was gradually raised to room temperature. After additionof water, the reaction mixture was extracted with ethyl acetate, and theorganic layer was washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane=1/2→1/1 (v/v)) to give the title compound as acolorless oil (556 mg, yield 97%).

Reference Synthetic Example^(a) 53(trans-4-Methoxycyclohexyl)(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone

The reactions in Reference Synthetic Example^(a) 10 were carried out insubstantially the same manners except thattrans-N,4-dimethoxy-N-methylcyclohexanecarboxamide was used instead ofN-methoxy-N,2-dimethylbenzamide to give the title compound as an ivorysolid (178 mg, yield 69%).

Reference Synthetic Examples^(a) 54 to 60

The reactions in Reference Synthetic Example^(a) 9 were carried out insubstantially the same manners except that4,4-difluoroxyclohexanecarboxylic acid,bicycle[2.2.1]heptane-2-carboxylic acid, cycloheptanecarboxylic acid,cyclobutanecarboxylic acid, cyclopentanecarboxylic acid,trans-4-(trifluoromethyl)cyclohexanecarboxylic acid orcis-4-(trifluoromethyl)cyclohexanecarboxylic acid was used instead of2-methylbenzoic acid to give the compounds of Reference SyntheticExamples^(a) 54 to 60. The names, morphologies and yields of thecompounds synthesized are shown in Table^(a) 5.

TABLE^(a) 5 Rf Compound Name Morphology Yield 544,4-difluoro-N-methoxy-N- colorless oil 63% methylcyclohexanecarboxamide55 N-methoxy-N-methylbicyclo[2.2.1]heptane- colorless oil 47%2-carboxamide 56 N-methoxy-N- colorless oil 49%methylcycloheptanecarboxamide 57 N-methoxy-N- colorless oil 57%methylcyclobutanecarboxamide 58 N-methoxy-N- colorless oil 45%methylcyclopentanecarboxamide 59 trans-N-methoxy-N-methyl-4- colorlesssolid 82% (trifluoromethyl)cyclohexanecarboxamide 60 cis N methoxy Nmethyl 4 colorless oil 72% (trifluoromethyl)cyclohexanecarboxamide

Reference Synthetic Examples^(a) 61 To 67

The reactions in Reference Synthetic Example^(a) 10 were carried out insubstantially the same manners except that the compounds obtained inReference Synthetic Examples^(a) 54 to 60 were used instead ofN-methoxy-N,2-dimethylbenzamide to give the compounds of ReferenceSynthetic Examples^(a) 61 to 67. The names, morphologies and yields ofthe compounds synthesized are shown in Table^(a) 6.

TABLE^(a) 6 Rf Compound Name Morphology Yield 61 (4,4difluorocyclohexyl) (7H-pyrrolo[2,3- yellow solid 44%d]pyrimidin-4-yl)methanone 62 bicyclo[2.2.1]heptan-2-yl(7H-pyrrolo[2,pale yellow 66% 3-d]pyrimidin-4-yl)methanone solid 63cycloheptyl(7H-pyrrolo[2,3-d]pyrimidin- pale yellow 76% 4-yl)methanonesolid 64 cyclobutyl(7H-pyrrolo[2,3-d]pyrimidin-4- pale yellow 38%yl)methanone solid 65 cyclopentyl(7H-pyrrolo[2,3-d]pyrimidin- paleyellow 73% 4-yl)methanone solid 66(7H-pyrrolo[2,3-d]pyrimidin-4-yl)[trans- milky solid 65%4-(trifluoromethyl)cyclohexyl]methanone 67(7H-pyrrolo[2,3-d]pyrimidin-4-yl[cis-4- milky solid 53%(trifluoromethyl)cyclohexyl]methanone

Reference Synthetic Example^(a) 68[trans-4-(tert-Butyldiphenylsilyl)oxy]-N-methoxyl-N-methylcyclohexanecarboxamide

trans-4-Hydroxy-N-methoxy-N-methylcyclohexanecarboxamide (1.35 g, 7.21mmol) obtained in Reference Synthetic Example^(a) 51 inN,N-dimethylformamide (48 mL) was stirred with imidazole (598 mg, 8.65mmol) and tert-butylchlorodiphenylsilane (2.07 mL, 7.93 mmol) for 4hours under cooling with ice. After addition of water, the reactionmixture was extracted with ethyl acetate, and the organic layer waswashed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=15/1→7/1→3/1 (v/v)) to give the title compound as a colorlessoil (1.52 g, yield 50%).

Reference Synthetic Example^(a) 69{trans-4-[(tert-Butyldiphenylsilyl)oxy]cyclohexyl}(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone

The reactions in Reference Synthetic Example^(a) 10 were carried out insubstantially the same manners except thattrans-4-[(tert-butyldiphenylsilyl)oxy]-N-methoxy-N-methylcyclohexanecarboxamidewas used instead of N-methoxy-N,2-dimethylbenzamide to give the titlecompound as a yellow amorphous (1.34 g, yield 78%).

Reference Synthetic Example^(a) 701-{4-[(tert-Butyldiphenylsilyl)oxy]cyclohexyl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

The reactions in Synthetic Example^(a) 5 were carried out insubstantially the same manners except that{trans-4-[(tert-butyldiphenylsilyl)oxy]cyclohexyl}(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanonewas used instead of (7H-pyrrolo[2,3-d]pyrimidin-4-yl)(o-tolyl)methanoneto give the title compound as a pale yellow solid (838 mg, yield 61%).

Reference Synthetic Example^(a) 714-Hydroxy-N-methoxy-N-methylcyclohexanecarboxamide

4-Hydroxycyclohexanecarboxylic acid (10.0 g, 69.4 mmol) andN,O-dimethylhydroxylamine hydrochloride (8.80 g, 90.2 mmol) indichloromethane (500 mL) was stirred with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17.3 g,90.2 mmol), 1-hydroxybenzotriazole (12.2 g, 90.2 mmol) andN,N-diisopropylethylamine (24.2 mL, 139 mmol) at room temperature forone day. After addition of water, the reaction mixture was extractedwith chloroform, and the organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=1/1 (v/v)→ethyl acetate) to givethe title compound as a yellow oil (9.07 g, yield 70%).

Reference Synthetic Example^(a) 724-1(tert-Butyldimethylsilyl)oxyl-N-methoxy-N-methylcyclohexanecarboxamide

4-Hydroxy-N-methoxy-N-methylcyclohexanecarboxamide (7.34 g, 39.2 mmol)in N,N-dimethylformamide (200 mL) was stirred with imidazole (4.80 g,70.6 mmol) and tert-butylchlorodimethylsilane (7.70 g, 51.0 mmol) atroom temperature for one day. After addition of water, the reactionmixture was extracted with ethyl acetate, and the organic layer waswashed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=25/1→4/1 (v/v)) to give the title compound as a colorless oil(8.68 g, yield 73%).

Reference Synthetic Example^(a) 73{4-[(tert-Butyldimethylsilyl)oxy]cyclohexyl}(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone

The reactions in Reference Synthetic Example^(a) 10 were carried out insubstantially the same manners except that4-[(tert-butyldimethylsilyl)oxy]-N-methoxy-N-methylcyclohexanecarboxamidewas used instead of N-methoxy-N,2-dimethylbenzamide to give the titlecompound as a pale yellow solid (7.14 g, yield 69%).

Reference Synthetic Example^(a) 741-{4-[(tert-Butyldimethylsilyl)oxy]cyclohexyl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[,1,5-c]pyrimidine

The reactions in Synthetic Example^(a) 5 were carried out insubstantially the same manners except that{4-[(tert-butyldiphenylsilyl)oxy]cyclohexyl}(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanonewas used instead of (7H-pyrrolo[2,3-d]pyrimidin-4-yl)(o-tolyl)methanoneto give the title compound as a pale yellow solid (5.20 g, yield 70%).

Reference Synthetic Example^(a) 754-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanol

1-{4-[(tert-Butyldimethylsilyl)oxy]cyclohexyl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine(500 mg, 1.35 mmol) in a mixture of dichloromethane (5 mL) and methanol(5 mL) was stirred with pyridinium p-toluenesulfonate (338 mg, 1.35mmol) at 60° C. for 3 hours. The reaction mixture was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography (hexane/ethyl acetate=4/1→1/1 (v/v)→ethyl acetate) togive the title compound as a colorless solid (259 mg, yield 75%).

Reference Synthetic Example^(a) 76 Benzyl4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)piperidine-1-carboxylate

The reactions in Reference Synthetic Example^(a) 18 were carried out insubstantially the same manners except that benzyl4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate obtained inReference Synthetic Example^(a) 43 was used instead of benzyl3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate to give the titlecompound as a yellow oil (49.6 mg, yield 71%).

Reference Synthetic Example^(a) 77 Benzyl4-[amino(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl]piperidine-1-carboxylate

The reactions in Reference Synthetic Example^(a) 7 were carried out insubstantially the same manners except that benzyl4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)piperidine-1-carboxylatewas used instead ofcyclohexyl(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanoneto give the title compound as a colorless oil (33.2 mg, yield 67%).

Reference Synthetic Example^(a) 78 Benzyl4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-imidazo[1,5-c]pyrrolo[3,2-e]pyrimidin-1-yl)piperidine-1-carboxylate

The reactions in Reference Synthetic Example^(a) 20 were carried out insubstantially the same manners except that benzyl4-[amino(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl]piperidine-1-carboxylatewas used instead of benzyl3-[amino(7-{[2-(trimethylsilyl)ethoxy]methy}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl]piperidine-1-carboxylateto give a brown oily mixture containing the title compound (16.0 mg).The resulting mixture was used for the next step without purification.

Reference Synthetic Example^(a) 79 Benzyl4-[amino(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl]piperidine-1-carboxylate

Benzyl4-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)piperidine-1-carboxylate (50.0mg, 0.137 mmol) obtained in Reference Synthetic Example^(a) 44 inmethanol (1 mL) was stirred with aqueous hydroxylamine (300 μL) at 75°C. for 4 hours and allowed to cool to room temperature. After additionof water and saturated aqueous ammonium chloride, the reaction mixturewas extracted with chloroform. The organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure to givea colorless oil. The oil was dissolved in methanol (3 mL), stirred withzinc powder (45.0 mg, 0.685 mmol) and acetic acid (24.0 μL, 0.411 mmol)at 75° C. for 3 hours and allowed to cool to room temperature. Afteraddition of water and saturated aqueous sodium hydrogen carbonate, thereaction mixture was extracted with chloroform. The organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure to give the title compound as a yellow oil (50.0 mg, yield99%).

Reference Synthetic Example^(a) 80Piperidin-4-yl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone hydrochloride

tert-Butyl4-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)piperidine-1-carboxylate (840mg, 2.54 mmol) obtained in Reference Synthetic Example^(a) 39 in1,4-dioxane (3 mL) was stirred with 4 M hydrogen chloride-1,4-dioxane (3mL) at room temperature for one day. The resulting solid was collectedby filtration to give the title compound as a brown solid (677 mg, yield99%).

Reference Synthetic Example^(a) 81(7H-Pyrrolo[2,3-d]pyrimidin-4-yl){1-[4-(trifluoromethyl)benzyl]piperidin-4-yl}methanone

Piperidin-4-yl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone hydrochloride(60.0 mg, 0.224 mmol) in acetonitrile (3 mL) was stirred with4-(trifluoromethyl)benzyl bromide (70.0 mg, 0.292 mmol) andN,N-diisopropylethylamine (144 μL, 0.784 mmol) at 60° C. for 2 hours andallowed to cool to room temperature. After addition of water andsaturated aqueous ammonium chloride, the reaction mixture was extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate=1/1(v/v)) to give the title compound as a pale yellow solid (65.0 mg, yield75%).

Reference Synthetic Example^(a) 82(7H-Pyrrolo[2,3-d]pyrimidin-4-yl){1-[4-(trifluoromethyl)benzyl]piperidin-4-yl}methanamine

The reactions in Reference Synthetic Example^(a) 79 were carried out insubstantially the same manners except that(7H-pyrrolo[2,3-d]pyrimidin-4-yl){1-[4-(trifluoromethyl)benzyl]piperidin-4-yl}methanonewas used instead of benzyl4-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)piperidine-1-carboxylate togive the title compound as a colorless solid (65.0 mg, yield 99%).

Reference Synthetic Example^(a) 83 Benzyl3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate

The reactions in Reference Synthetic Example^(a) 43 were carried out insubstantially the same manners except that azetidine-3-carboxylic acidwas used instead of piperidine-4-carboxylic acid to give the titlecompound as a colorless oil (1.18 g, yield 21%).

Reference Synthetic Example^(a) 84 Benzyl3-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)azetidine-1-carboxylate

The reactions in Reference Synthetic Example^(a) 10 were carried out insubstantially the same manners except that benzyl3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate was used instead ofN-methoxy-N,2-dimethylbenzamide to give the title compound as a yellowsolid (656 mg, yield 46%).

Reference Synthetic Example^(a) 854-(Hydroxymethyl)-N-methoxy-N-methylbenzamide

4-(Hydroxymethyl)benzoic acid (3.00 g, 19.7 mmol) andN,O-dimethylhydroxylamine hydrochloride (2.31 g, 23.7 mmol) inchloroform (30 mL) was stirred with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.54 g,23.7 mmol), 1-hydroxybenzotriazole (3.20 g, 23.7 mmol) andN,N-diisopropylethylamine (8.04 mL, 47.3 mmol) at room temperature forone day. After addition of water, the reaction mixture was extractedwith ethyl acetate, and the organic layer was washed with saturatedaqueous sodium chloride, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give a mixture containing thetitle compound as a colorless oil (4.20 g). The resulting mixture wasused for the next step.

Reference Synthetic Example^(a) 864-{[(tert-Butyldimethylsilyl)oxy]methyl}-N-methoxy-N-methylbenzamide

4-(Hydroxymethyl)-N-methoxy-N-methylbenzamide (4.20 g) obtained inReference Synthetic Example^(a) 85 in N,N-dimethylformamide (10 mL) wasstirred with imidazole (4.00 g, 59.2 mmol) andtert-butylchlorodimethylsilane (3.60 g, 23.7 mmol) at room temperaturefor one day. After addition of water, the reaction mixture was extractedwith ethyl acetate, and the organic layer was washed with saturatedaqueous sodium chloride, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=5/1→3/1 (v/v)) to givethe title compound as a colorless oil (5.45 g, yield 89% (two steps)).

Reference Synthetic Example^(a) 87(4-{[(tert-Butyldimethylsilyl)oxy]methyl}phenyl)(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone

The reactions in Reference Synthetic Example^(a) 10 were carried out insubstantially the same manners except that4-{[(tert-butyldimethylsilyl)oxy]methyl}-N-methoxy-N-methylbenzamide wasused instead of N-methoxy-N,2-dimethylbenzamide to give the titlecompound as a pale yellow solid (4.40 g, yield 68%).

Reference Synthetic Example^(a) 881-(4-{[(tert-Butyldimethylsilyl)oxy]methyl}phenyl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

The reactions in Synthetic Example^(a) 5 were carried out insubstantially the same manners except that(4-{[(tert-butyldimethylsilyl)oxy]methyl}phenyl)(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanonewas used instead of (7H-pyrrolo[2,3-d]pyrimidin-4-yl)(o-tolyl)methanoneto give the title compound as a colorless solid (3.58 g, yield 79%).

Reference Synthetic Example^(a) 89cis-4-(Hydroxymethyl)-N-methoxy-N-methylcyclohexanecarboxamide

The reactions in Reference Synthetic Example^(a) 85 were carried out insubstantially the same manners except thatcis-4-(hydroxymethyl)cyclohexanecarboxylic acid was used instead of4-(hydroxymethyl)benzoic acid to give a mixture containing the titlecompound as a colorless oil (3.17 g). The resulting mixture was used forthe next step.

Reference Synthetic Example^(a) 90cis-4-{[(tert-Butyldimethylsilyl)oxy]methyl}-N-methoxy-N-methylcyclohexanecarboxamide

The reactions in Reference Synthetic Example^(a) 86 were carried out insubstantially the same manners except thatcis-4-(hydroxymethyl)-N-methoxy-N-methylcyclohexanecarboxamide obtainedin Reference Synthetic Example^(a) 89 was used instead of4-(hydroxymethyl)-N-methoxy-N-methylbenzamide to give the title compoundas a colorless oil (5.3 g, yield 89% (two steps)).

Reference Synthetic Example^(a) 91(cis-4-{[(tert-Butyldimethylsilyl)oxy]methyl}cyclohexyl)(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone

The reactions in Reference Synthetic Example^(a) 10 were carried out insubstantially the same manners except thatcis-4-{[(tert-butyldimethylsilyl)oxy]methyl}-N-methoxy-N-methylcyclohexanecarboxamidewas used instead of N-methoxy-N,2-dimethylbenzamide to give the titlecompound as a pale yellow solid (4.50 g, yield 72%).

Reference Synthetic Example^(a) 921-(trans-4-{[(tert-Butyldimethylsilyl)oxy]methyl}cyclohexyl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

The reactions in Synthetic Example^(a) 5 were carried out insubstantially the same manners except that(cis-4-{[(tert-Butyldimethylsilyl)oxy]methyl}cyclohexyl)(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanonewas used instead of (7H-pyrrolo[2,3-d]pyrimidin-4-yl)(o-tolyl)methanoneto give the title compound as a pale yellow solid (3.49 g, yield 75%).(although the cis-isomer was used as the starting material, only thetrans-isomer of the title compound was obtained.)

Reference Synthetic Example^(a) 935-(Bromomethyl)thiophene-2-carbonitrile

5-Methylthiophene-2-carbonitrile (500 mg, 4.06 mmol) in carbontetrachloride (10 mL) was stirred with N-bromosuccinimide (867 mg, 4.87mmol) and 2,2′-azobis(isobutyronitrile) (133 mg, 0.810 mmol) at 60° C.for 4.5 hours and allowed to cool to room temperature. After addition ofsaturated aqueous sodium thiosulfate, the reaction mixture was extractedwith chloroform, and the organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=2/1→1/1 (v/v)) to give the title compound as a yellow oil (186mg, yield 23%).

Reference Synthetic Example^(a) 944-{[4-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)piperidin-1-yl]methyl}benzonitrile

The reactions in Reference Synthetic Example^(a) 81 were carried out insubstantially the same manners except that 4-(bromomethyl)benzonitrilewas used instead of 4-(trifluoromethyl)benzyl bromide to give the titlecompound as a pale yellow solid (150.9 mg, yield 65%).

Reference Synthetic Example^(a) 954-{[4-(7{[2-(Trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)piperidin-1-yl]methyl}benzonitrile

The reactions in Reference Synthetic Example^(a) 15 were carried out insubstantially the same manners except that4-{[4-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)piperidin-1-yl]methyl}benzonitrilewas used instead of 4-iodo-7H-pyrrolo[2,3-d]pyrimidine to give the titlecompound as a yellow oil (124.1 mg, yield 75%).

Reference Synthetic Example^(a) 964-({4-[Amino(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl]piperidin-1-yl}methyl)benzonitrile

The reactions in Reference Synthetic Example^(a) 7 were carried out insubstantially the same manners except that4-({4-[amino(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl]piperidin-1-yl}methyl)benzonitrilewas used instead ofcyclohexyl(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanoneto give the title compound as a yellow oil (42.9 mg, yield 34%).

Reference Synthetic Example^(a) 974-{[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-imidazo[1,5-c]pyrrolo[3,2-e]pyrimidin-1-yl)piperidin-1-yl]methyl}benzonitrile

The reactions in Reference Synthetic Example^(a) 20 were carried out insubstantially the same manners except that4-({4-[amino(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl]piperidin-1-yl}methyl)benzonitrilewas used instead of benzyl3-[amino(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl]piperidine-1-carboxylateto give a brown oil containing the title compound (37.4 mg). Theresulting mixture was used for the next step.

Reference Synthetic Example^(a) 98 Benzyl3-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate

Triethylamine (1.68 mL, 12.0 mmol) was added dropwise to1-[(benzyloxy)carbonyl]pyrrolidine-3-carboxylic acid (1.00 g, 4.01mmol), N,O-dimethylhydroxylamine hydrochloride (782 mg, 8.02 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.54 g,8.02 mmol) and 1-hydroxybenzotriazole (1.08 g, 8.02 mmol) in chloroform(20 mL), and the reaction mixture was stirred at room temperature for 16hours. After addition of water, the reaction mixture was extracted withchloroform, and the organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=1/1→3/7 (v/v)) to give the title compound as a yellow oil (1.11g, yield 95%).

Reference Synthetic Example^(a) 99 Benzyl3-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)pyrrolidine-1-carboxylate

The reactions in Reference Synthetic Example^(a) 10 were carried out insubstantially the same manners except that benzyl3-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate was used insteadof N-methoxy-N,2-dimethylbenzamide to give a pale yellow solidcontaining the title compound (216 mg). The resulting mixture was usedfor the next step.

Reference Synthetic Example^(a) 1003-Amino-2-(4-chlorophenyl)-1,1,1-trifluoropropan-2-ol

1-(4-Chlorophenyl)-2,2,2-trifluoroethanone (2.00 g, 9.59 mmol) innitromethane (10 mL) was stirred with potassium carbonate (1.32 g, 9.59mmol) at room temperature for 1 hour. After addition of water, thereaction mixture was extracted with ethyl acetate, and the organic layerwas dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The resulting residue (pale yellow amorphous, 3.3 g)was dissolved in ethanol (52 mL), then 6 M hydrochloric acid was addeddropwise under cooling with ice, and zinc powder (3.13 g, 48.0 mmol) wasgradually added. The reaction mixture was stirred for one day while thetemperature was gradually raised to room temperature, and filteredthrough Celite. The filtrate was concentrated under reduced pressure.The residue was mixed with 28 wt % aqueous ammonia and extracted withchloroform, and the organic layer was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=3/1→1/1 (v/v)) to give the title compound as a colorless solid(609 mg, yield 26%).

Reference Synthetic Example^(a) 1013-Amino-1,1,1-trifluoro-2-phenylpropan-2-ol

The reactions in Reference Synthetic Example^(a) 100 were carried out insubstantially the same manners except that2,2,2-trifluoro-1-phenylethanone was used instead of1-(4-chlorophenyl)-2,2,2-trifluoroethanone to give the title compound asa colorless solid (54 mg, yield 46%).

Reference Synthetic Example^(a) 1023-Amino-1,1,1-trifluoro-2-(4-fluorophenyl)propan-2-ol

n-Butyllithium (2.66 M solution in hexane, 12.4 mL, 33.0 mmol) was addeddropwise to 1-bromo-4-fluorobenzene (5.25 g, 30.0 mmol) intetrahydrofuran (50 mL) cooled to −78° C., and the reaction mixture wasstirred at −78° C. for 30 minutes, mixed with ethyl2,2,2-trifluoroacetate (4.64 mL, 45 mmol) at −78° C. and then stirredfor another 30 minutes while the temperature was gradually raised toroom temperature. The reaction mixture was stirred with nitromethane(3.25 mL, 60 mmol) at room temperature for 30 minutes. The resultingreaction mixture was added to 1 M hydrochloric acid (50 mL) andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate=5/1(v/v/)) to give a colorless oil. The colorless oil was dissolved inethanol (25 mL) and stirred with 10% palladium-carbon (1 g) at roomtemperature for one day under a hydrogen atmosphere. The reactionmixture was filtered through Celite, and the filtrate was concentratedunder reduced pressure to give the title compound as a colorless solid(4.52 g, yield 68% (three steps)).

Reference Synthetic Example^(a) 103 2-[4-(Trifluoromethyl)phenyl]oxirane

Trimethylsulfonium iodide (4.08 g, 20.0 mmol) in dimethyl sulfoxide (15mL) was stirred with sodium hydride (55 wt % dispersion in mineral oil,873 mg, 20.0 mmol) at room temperature for 1 hour and then with4-(trifluoromethyl)styrene (2.96 g, 17.0 mmol) in dimethyl sulfoxide (10mL) at room temperature for 2 hours. After addition of water, thereaction mixture was extracted with ethyl acetate, and the organic layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate=9/1 (v/v)) to give the title compound as acolorless oil (2.59 g, yield 81%).

Reference Synthetic Example^(a) 1041-(Piperidin-4-yl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidineacetate

5% Palladium-carbon (0.87 g) was added to benzyl4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidine-1-carboxylate(4.88 g, 13.0 mmol) obtained in Synthetic Example^(a) 26 in a mixture ofacetic acid (60 mL), water (6 mL) and ethanol (10 mL), and after thenthe reaction system was flushed with hydrogen, the reaction mixture wasstirred at room temperature for one day and then filtered. The filtratewas concentrated, and the resulting yellow solid was washed with ethanolto give the title compound as a colorless solid (3.30 g, yield 84%).

Reference Synthetic Example^(a) 105 2-(4-Formylphenoxy)acetonitrile

4-Hydroxybenzaldehyde (244 mg, 2.00 mmol) in N,N-dimethylformamide (5mL) was mixed with sodium hydride (60 wt % dispersion in liquidparaffin, 120 mg, 3.00 mmol) and chloroacetonitrile (189 μL, 3.00 mmol)under cooling with ice and then stirred at 50° C. for 3 hours. Thereaction mixture was allowed to cool to room temperature and mixed withsaturated aqueous ammonium chloride and extracted with ethyl acetate.The organic layer was washed with 1M aqueous sodium hydroxide, driedover anhydrous sodium sulfate and concentrated under reduced pressure togive the title compound as a brown oil (128 mg, yield 40%).

Reference Synthetic Example^(a) 106 4-(Bromomethyl)benzamide

4-(Bromomethyl)benzoic acid (300 mg, 1.40 mmol) in ethyl acetate (5 mL)was stirred with thionyl chloride (249 μL, 3.50 mmol) at 75° C. for 9hours. The reaction mixture was allowed to cool to room temperature andconcentrated under reduced pressure. The residue was dissolved indichloromethane (5 mL) and stirred with 28% ammonia aqueous solution(380 μL, 5.60 mmol) under cooling with ice for 80 minutes. The reactionmixture was mixed with water, and the precipitate was collected byfiltration, washed with dichloromethane to give the title compound as acolorless solid (274 mg, yield 91%).

Reference Synthetic Example^(a) 1075-(Bromomethyl)-2-(trifluoromethyl)benzonitrile

5-Methyl-2-(trifluoromethyl)benzonitrile (200 mg, 1.08 mmol) in1,2-dichloroethane (3 mL) was stirred with N-bromosuccinimide (192 mg,1.08 mmol) and azobisisobutyronitrile (36.1 mg, 0.22 mmol) at 80° C. for2 hours. The reaction mixture allowed to cool to room temperature andwas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane→ethyl acetate/hexane=1/3 (v/v))to give the title compound as a colorless solid (140 mg, yield 49%).

Reference Synthetic Example^(a) 108 4-(Bromomethyl)phthalonitrile

The reactions in Reference Synthetic Example^(a) 107 were carried out insubstantially the same manners except that 4-methylphthalonitrile wasused instead of 5-methyl-2-(trifluoromethyl)benzonitrile to give thetitle compound as a colorless solid (163 mg, yield 52%).

Reference Synthetic Example^(a) 1094-(Bromomethyl)-2-(trifluoromethyl)benzonitrile

The reactions in Reference Synthetic Example^(a) 107 were carried out insubstantially the same manners except that4-methyl-2-(trifluoromethyl)benzonitrile was used instead of5-methyl-2-(trifluoromethyl)benzonitrile to give the title compound as acolorless solid (177 mg, yield 62%).

Reference Synthetic Example^(a) 110 tert-Butyl 4-cyanophenethylcarbamate

2-(4-Bromophenyl)ethylamine (2.00 g, 10.0 mmol) in tetrahydrofuran (5mL) was mixed with Di-tert-butyl dicarbonate (2.20 g, 10.0 mmol) undercooling with ice and then stirred at room temperature for one day. Afteraddition of water, the reaction mixture was extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The resulting residue (900 mg) wasdissolved in N,N-dimethylformamide (30 mL) and mixed with zinc cyanide(705 mg, 60.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (347mg, 0.300 mmol), and the reaction mixture was stirred at 150° C. for 20minutes under microwave irradiation. The resulting reaction mixture wasallowed to cool to room temperature, mixed with saturated aqueousammonium chloride and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate=10/1→4/1 (v/v)) to give the title compound as apale yellow solid (305 mg, yield 41%).

Reference Synthetic Example^(a) 111 4-(2-Aminoethyl)benzonitrile

tert-Butyl 4-cyanophenethylcarbamate (305 mg, 1.24 mmol) indichloromethane (4 mL) was mixed with trifluoroacetic acid (3.50 mL,47.1 mmol) under cooling with ice and then stirred at room temperaturefor 30 minutes. The reaction mixture was concentrated under reducedpressure, mixed with saturated aqueous potassium carbonate and extractedwith ethyl acetate. The organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous sodium sulfate and concentratedunder reduced pressure to give the title compound as a pale orange solid(72.5 mg, yield 40%).

Reference Synthetic Example^(a) 112 tert-Butyl3-oxoazetidine-1-carboxylate

tert-Butyl 3-hydroxyazetidine-1-carboxylate (4.02 g, 23.2 mmol) indichloromethane (305 mL) was mixed with Dess-Martin Periodinane (9.55 g,22.5 mmol) under cooling with ice and then stirred at room temperaturefor 3 hours. After addition of 10% aqueous sodium thiosulfate andsaturated aqueous sodium hydrogen carbonate under cooling with ice, thereaction mixture was extracted with chloroform, and the organic layerwas washed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (hexane/ethylacetate=2/1 (v/v)) to give the title compound as a colorless solid (3.39g, yield 85%).

Reference Synthetic Example^(a) 113 tert-Butyl3-hydroxy-3-methylazetidine-1-carboxylate

Methylmagnesium bromide— tetrahydrofuran solution (1.12 M, 3.90 mL, 4.38mmol) was added dropwise to tert-butyl 3-oxoazetidine-1-carboxylate (500mg, 2.92 mmol) in tetrahydrofuran (5 mL) under cooling with ice andstirred for 90 minutes. After addition of saturated aqueous ammoniumchloride, the reaction mixture was extracted with ethyl acetate, and theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=2/1→1/1 (v/v)) to give the titlecompound as a colorless solid (224 mg, yield 41%).

Reference Synthetic Example^(a) 114 3-Methylazetidin-3-ol hydrochloride

tert-Butyl 3-hydroxy-3-methylazetidine-1-carboxylate (224 mg, 1.20 mmol)in ethyl acetate (1 mL) was mixed with 4 M hydrogen chloride-1,4-dioxanesolution (3.0 mL) under cooling with ice and then stirred at roomtemperature for 1 hour. The reaction mixture was concentrated underreduced pressure to give a mixture containing the title compound(colorless oil, 162 mg). The mixture was used for the next step withoutfurther purification.

Reference Synthetic Example^(a) 115 3-(Trifluoromethyl)azetidin-3-olhydrochloride

tert-Butyl 3-oxoazetidine-1-carboxylate (500 mg, 2.92 mmol) obtained inReference Synthetic Example^(a) 112 and (trifluoromethyl)trimethysilane(0.648 mL, 4.38 mmol) in tetrahydrofuran (10 mL) were mixed withtetrabutylammonium fluoride-tetrahydrofuran solution (1 M, 0.291 mL,0.291 mmol) under cooling with ice and then stirred at room temperaturefor 1 hour. After addition of saturated aqueous ammonium chloride, thereaction mixture was extracted with diethyl ether, and the organic layerwas dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was mixed with ethyl acetate (5 mL) and 1Maqueous citric acid (5 mL) and stirred at room temperature for 1 hour.After addition of water, the reaction mixture was extracted with diethylether. The organic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The resulting residue was dissolvedin ethyl acetate (1.0 mL), mixed with 4 M hydrogen chloride-1,4-dioxanesolution (4 mL) under cooling with ice and then stirred at roomtemperature for 22 hours. The reaction mixture was concentrated underreduced pressure, and the precipitate was washed with ethyl acetate togive the title compound as a white solid (340 mg, yield 66% (2 steps)).

Reference Synthetic Example^(a) 116 tert-Butyl3-(2,2,2-trifluoroethoxy)azetidine-1-carboxylate

Sodium hydride (55 wt % dispersion in liquid paraffin, 151 mg, 3.46mmol) in N,N-dimethylformamide (5 mL) was mixed with tert-butyl3-hydroxyazetidine-1-carboxylate (500 mg, 2.89 mmol) inN,N-dimethylformamide (3 mL) under cooling with ice and stirred for 30minutes, and the resulting reaction mixture was mixed with2,2,2-trifluoroethyl trifluoromethanesulfonate (0.499 mL, 3.46 mmol)under cooling with ice and then stirred at room temperature for 5 hours.After addition of water, the reaction mixture was extracted with ethylacetate, and the organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1→1/1 (v/v)) to give the titlecompound as a colorless solid (350 mg, yield 48%).

Reference Synthetic Example^(a) 117 3-(2,2,2-Trifluoroethoxy)azetidinehydrochloride

tert-Butyl 3-(2,2,2-trifluoroethoxy)azetidine-1-carboxylate (350 mg,1.37 mmol) in ethyl acetate (1.0 mL) was mixed with 4 M hydrogenchloride-1,4-dioxane solution (3.0 mL) under cooling with ice and thenstirred at room temperature for 2 hours. The reaction mixture wasconcentrated to give a mixture containing the title compound as acolorless oil (224 mg). The mixture was used for next step withoutfurther purification.

Reference Synthetic Example^(a) 1183-Amino-1,1,1-trifluoro-2-(pyridin-3-yl)propan-2-ol

Isopropylmagnesium chloride-lithium chloride complex-tetrahydrofuransolution (1.3 M, 20.7 mL, 27.0 mmol) was added dropwise to5-bromo-2-chloropyridine (5.20 g, 27.0 mmol) in tetrahydrofuran (40 mL)under cooling with ice, and the reaction mixture was stirred for 30minutes and then mixed with ethyl 2,2,2-trifluoroacetate (11.5 g, 81.0mmol) under cooling with ice and stirred at room temperature for 10minutes. After addition of 1M hydrochloric acid, the reaction mixturewas extracted with ethyl acetate, and the organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure to givea yellow oil. The yellow oil was dissolved in nitromethane (30 mL) andstirred with potassium carbonate (3.73 g, 27.0 mmol) at room temperaturefor 30 minutes. The reaction mixture was added to 1M hydrochloric acidand extracted with ethyl acetate, and the organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=3/1 (v/v)) to give a yellow oil. The yellow oil was dissolved intetrahydrofuran (20 mL), mixed with 10% palladium-carbon (600 mg) andtriethylamine (2.60 mL, 18.7 mmol) and then stirred at room temperaturefor one day under a hydrogen atmosphere. The reaction mixture wasfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate→ethyl acetate/methanol/triethylamine=9/1/1 (v/v/v)) to give thetitle compound as a colorless solid (913 mg, yield 31%(4 steps)).

Reference Synthetic Example^(a) 1193-Amino-1,1,1-trifluoro-2-[4-(methylthio)phenyl]propan-2-ol

The reactions in Reference Synthetic Example^(a) 102 were carried out insubstantially the same manners except that(4-bromomethyl)(methyl)sulfane was used instead of1-bromo-4-fluorobenzene to give the title compound as a colorless solid(2.61 g, yield 64%).

Reference Synthetic Example^(a) 1203-Amino-1,1,1-trifluoro-2-(6-methoxypyridin-3-yl)propan-2-ol

The reactions in Reference Synthetic Example^(a) 102 were carried out insubstantially the same manners except that 5-bromo-2-methoxypyridine wasused instead of 1-bromo-4-fluorobenzene to give the title compound as acolorless solid (1.52 g, yield 76%).

Reference Synthetic Example^(a) 1213-Amino-1,1,1-trifluoro-2-(4-methoxyphenyl)propan-2-ol

The reactions in Reference Synthetic Example^(a) 100 were carried out insubstantially the same manners except that2,2,2-trifluoro-1-(4-methoxyphenyl)etanone was used instead of1-(4-Chlorophenyl)-2,2,2-trifluoroethanone to give the title compound asa colorless solid (823 mg, yield 36%).

Reference Synthetic Example^(a) 1223-Amino-2-(3,4-dimethoxyphenyl)-1,1,1-trifluoropropan-2-ol

The reactions in Synthetic Example^(a) 100 were carried out insubstantially the same manners except that1-(3,4-dimethoxyphenyl)-2,2,2-trifluoroetanone was used instead of1-(4-Chlorophenyl)-2,2,2-trifluoroethanone to give the title compound asa colorless solid (532 mg, yield 39%).

Reference Synthetic Example^(a) 123 Ethyl(E)-3-(4-fluorophenyl)acrylate

4-Fluorobenzaldehyde (9.61 g, 80.0 mmol) in tetrahydrofuran (120 mL) wasmixed with ethyl 2-(diethoxyphosphoryl) acetate (17.9 g, 80.0 mmol)under cooling with ice, and then sodium ethoxide-ethanol solution (21 wt%, 44.8 mL, 120 mmol) was added dropwise to the reaction mixture undercooling with ice, and the resulting reaction mixture was stirred at roomtemperature for 2 hours. After addition of water, the reaction mixturewas extracted with ethyl acetate, and the organic layer dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=20/1→10/1 (v/v)) to give the title compound as a colorless oil(14.1 g, yield 91%).

Reference Synthetic Example^(a) 124 trans-Ethyl2-(4-fluorophenyl)cyclopropanecarboxylate

Trimethylsulfoxonium iodide (7.92 g, 36.0 mmol) in dimethyl sulfoxide(40 mL) was mixed with sodium hydride (55 wt % dispersion in mineraloil, 1.57 g, 36.0 mmol) under cooling with ice, stirred at roomtemperature for 1 hour and then stirred with (E)-ethyl3-(4-fluorophenyl)acrylate (5.83 g, 30.0 mmol) for 18 hours. Afteraddition of water, the reaction mixture was extracted with ethylacetate, and the organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=10/1) to give thetitle compound as a colorless oil (793 mg, yield 13%).

Reference Synthetic Example^(a) 1252-{[trans-2-(4-Fluorophenyl)cyclopropyl]methyl}isoindoline-1,3-dione

trans-Ethyl 2-(4-Fluorophenyl)cycloprpane-1-carboxylate (793 mg, 4.57mmol) in tetrahydrofuran (7 mL) was stirred with lithium aluminiumhydride (173 mg, 4.57 mmol) under cooling with ice for 10 minutes. Afteraddition of 1 M aqueous sodium hydroxide, the reaction mixture wasextracted with ethyl acetate, and the organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresulting residue was dissolved in tetrahydrofuran (10 mL), mixed withtriphenylphosphine (999 mg, 3.81 mmol), isoindoline-1,3-dione (560 mg,3.81 mmol) and azodicarboxylic acid diisopropyl ester-toluene solution(1.9 M, 2.00 mL, 3.81 mmol) under cooling with ice, and the reactionmixture was stirred at room temperature for 1 hour and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=5/1 (v/v)) to give the titlecompound as a colorless solid (975 mg, yield 87%(2 steps)).

Reference Synthetic Example^(a) 126[trans-2-(4-Fluorophenyl)cyclopropyl]methanamine

2-{[trans-2-(4-Fluorophenyl)cyclopropyl]methyl}isoindoline-1,3-dione(974 mg, 3.30 mmol) in ethanol (50 mL) was stirred with hydrazinemonohydrate (825 mg, 16.5 mmol) at 100° C. for 30 minutes. The reactionmixture was concentrated to give the title compound as a colorless oil(360 mg, yield 66%).

Reference Synthetic Example^(a) 127 4-Aminoadamantan-1-ol

Concentrated sulfuric acid (35 mL) was mixed with concentrated nitricacid (4.5 mL) and 2-adamanthylamine (5.10 g, 4.57 mmol) under coolingwith ice, and the reaction mixture was stirred at room temperature for 2hours. The reaction mixture was added to ice water and adjusted to pH 10with 7.5 M aqueous sodium hydroxide. After addition of water, thereaction mixture was extracted with chloroform, and the organic layerwas dried over anhydrous magnesium sulfate and concentrated underreduced pressure to give the title compound as a yellow solid (2.79 g,yield 61%).

Reference Synthetic Example^(a) 128 128a:Benzyl[(1R,2s,3S,5s,7s)-5-hydroxyadamantan-2-yl]carbamate 128b:Benzyl[(1R,2r,3S,5s,7s)-5-hydroxyadamantan-2-yl]carbamate

4-Aminoadamantan-1-ol (2.57 g, 15.4 mmol) in tetrahydrofuran (25 mL) wasmixed with benzyl chloroformate (2.30 mL, 16.1 mmol) and 1 M aqueoussodium hydroxide (16.0 mL, 16.0 mmol) under cooling with ice and thenstirred at room temperature for one day. After addition of 10% aqueouspotassium hydrogen sulfate, the reaction mixture was extracted withethyl acetate, and the organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=1/2 (v/v)) to givebenzyl[(1R,2S3S,5S,7S)-5-hydroxyadamantan-2-yl]carbamate (ReferenceSynthetic Example^(a) 128a; yellow oil, 1.72 g, yield 37%) in a morepolar fraction andbenzyl[(1R,2R,3S,5S,7S)-5-hydroxyadamantan-2-yl]carbamate (ReferenceSynthetic Example^(a) 128b; yellow oil, 2.24 g, yield 48%) in a lesspolar fraction.

Reference Synthetic Example^(a) 129(1s,3R,4s,5S,7s)-4-Aminoadamantan-1-ol

Benzyl[(1R,2s,3S,5s,7s)-5-hydroxyadamantan-2-yl]carbamate (318 mg, 1.05mmol) obtained in Reference Synthetic Example^(a) 128a and 5%palladium-carbon (63 mg) in methanol (2 mL) were stirred at roomtemperature for one day under a hydrogen atmosphere. The reactionmixture was filtered, and the filtrate was concentrated under reducedpressure to give the title compound as a colorless solid (144 mg, yield82%).

Reference Synthetic Example^(a) 130(1s,3R,4r,5S,7s)-4-Aminoadamantan-1-ol

Benzyl[(1R,2r,3S,5s,7s)-5-hydroxyadamantan-2-yl]carbamate (2.24 g, 7.46mmol) obtained in Reference Synthetic Example^(a) 128b and 5%palladium-carbon (700 mg) in methanol (30 mL) were stirred at roomtemperature for one day under a hydrogen atmosphere. The reactionmixture was filtered, and the filtrate was concentrated under reducedpressure to give the title compound as a colorless solid (1.29 g,quantitative yield).

Reference Synthetic Example^(a) 131 2-Bromo-2,2-difluoroethanaminehydrochloride

Borane tetrahydrofuran complex-tetrahydrofuran solution (1.06 M, 12.0mL, 12.6 mmol) was added dropwise to 2-bromo-2,2-difluoroacetamide (2.00g, 11.5 mmol) in tetrahydrofuran (20 mL) under cooling with ice, and theresulting reaction mixture was stirred at room temperature for 5 hours.After addition of ethanol (10 mL) and concentrated hydrochloric acid (7mL), the reaction mixture was concentrated under reduced pressure. Theprecipitate was collected by filtration to give the title compound as acolorless solid (1.60 g, yield 71%).

Reference Synthetic Example^(a) 132 4-Cyanophenethyl4-methylbenzenesulfonate

4-(2-Hydroxyethyl)benzonitrile (200 mg, 1.35 mmol) in tetrahydrofuran (4mL) was mixed with 4-methylbenzene-1-sulfonyl chloride (389 mg, 2.04mmol) and triethylamine (569 μL, 4.08 mmol) and stirred at roomtemperature for 1 day. After addition of water, the reaction mixture wasextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=9/1→3/1→1/1 (v/v)) to give the title compound as a colorlesssolid (174 mg, yield 43%).

Reference Synthetic Example^(a) 1334-{[(tert-Butyldimethylsilyl)oxy]methyl}-N-methoxy-N-methylcyclohexanecarboxamide

4-(Hydroxymethyl)cyclohexanecarboxic acid (25.0 g, 158 mmol) andN,O-dimethylhydroxylamine hydrochloride (23.1 g, 237 mmol) in chloroform(100 mL) were mixed with 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (36.4 g, 190 mmol), 1-hydroxybenzotriazole (5.00 g, 37.0mmol) and N,N-diisopropylethylamine (41.3 mL, 237 mmol) and stirred atroom temperature for 1 day. After addition of water, the reactionmixture was extracted with ethyl acetate. The organic layer was washedwith saturated sodium chloride, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was dissolved inN,N-dimethylformamide (100 mL) and mixed with imidazole (21.5 g, 316mmol) and tert-butylchlorodimethylsilane (26.2 g, 174 mmol). Thereaction mixture was stirred at room temperature for 1 day. Afteraddition of water, the reaction mixture was extracted with ethylacetate. The organic layer was washed with saturated sodium chloride,dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate=5/1→3/1 (v/v)) to give the title compound as acolorless oil (32.4 g, yield 65%).

Reference Synthetic Example^(a) 134(4-{[(tert-Butyldimethylsilyl)oxy]methyl}cyclohexyl)(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone

Isopropylmagnesium chloride-lithium chloride complex-tetrahydrofuransolution (1.3 M, 39.2 mL, 51.0 mmol) was added dropwise to4-iodo-7H-pyrrolo[2,3-d]pyrimidine (5.00 g, 20.4 mmol) obtained inReference Synthetic Example^(a) 1 in tetrahydrofuran (50 mL) at −50° C.,and stirred at −50° C. for 1 hour. The reaction mixture was mixed with4-{[(tert-butyldimethylsilyl)oxy]methyl}-N-methoxy-N-methylcyclohexanecarboxamide(6.44 g, 20.4 mmol) in tetrahydrofuran (30 mL) at −50° C. and thenstirred at room temperature for 23 hours. After addition of saturatedaqueous ammonium chloride, the reaction mixture was extracted with ethylacetate. The organic layer was washed with saturated sodium chloride,dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate=3/1 (v/v)) to give the title compound as acolorless oil (5.14 g, yield 67%).

Reference Synthetic Example^(a) 135 135a:1-(cis-4-{[(tert-Butyldimethylsilyl)oxy]methyl}cyclohexyl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine135b:1-(trans-4-{[(tert-Butyldimethylsilyl)oxy]methyl}cyclohexyl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

(4-{[(tert-Butyldimethylsilyl)oxy]methyl}cyclohexyl)(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone(9.23 g, 24.7 mmol) in methanol (200 mL) was mixed with hydrazinemonohydrate (38.0 mL, 618 mmol) and then stirred at 80° C. for 3 hours.The reaction mixture was allowed to cool to room temperature and mixedwith ethyl acetate, washed with water and saturated sodium chloride. Theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was dissolved in chloroform (240 mL)and mixed with manganese(IV) oxide (10.7 g, 124 mmol). The reactionmixture was stirred at 70° C. for 1 day. The reaction mixture wasfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (hexane/ethylacetate=3/1 (v/v)) to give1-(cis-4-{[(tert-butyldimethylsilyl)oxy]methyl)}cyclohexyl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine(Reference Synthetic Example^(a) 135a; pale yellow solid, 670 mg, yield7%) in a less polar fraction and1-(trans-4-{[(tert-butyldimethylsilyl)oxy]methyl)}cyclohexyl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine(Reference Synthetic Example^(a) 135b, pale yellow solid, 5.02 g, yield52%) in a more polar fraction.

Reference Synthetic Example^(a) 136 Cyclopropylamine hydrochloride

Cyclopropylamine (0.600 mL, 8.76 mmol) was mixed with 1 M hydrogenchloride-diethylether solution (10 mL) under cooling with ice andstirred for 2 hours. The reaction mixture was concentrated under reducedpressure, and the precipitate was washed with diethyl ether to give thetitle compound as a colorless solid (686 mg, yield 84%).

Reference Synthetic Example^(a) 137 tert-Butyl3-(dimethylamino)azetidine-1-carboxylate

tert-Butyl 3-oxoazetidine-1-carboxylate (300 mg, 1.75 mmol) obtained inReference Synthetic Example^(a) 112 in methanol (15 mL) was mixed withacetic acid (1.0 mL), dimethylamine-tetrahydrofuran solution (2.0M, 1.31mL, 2.63 mmol) and 2-picoline borane (280 mg, 2.63 mmol). The reactionmixture was stirred at room temperature for 1 day. After addition of 1Maqueous hydrogen chloride, the reaction mixture was extracted with ethylacetate. The aqueous layer was adjusted to pH 10 with 1 M aqueous sodiumhydroxide and extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure togive the title compound as a colorless solid (134 mg, yield 90%).

Reference Synthetic Example^(a) 138 tert-Butyl3-[ethyl(methyl)amino]azetidine-1-carboxylate

The reactions in Reference Synthetic Example^(a) 137 were carried out insubstantially the same manners except that N-methylethanaminehydrochloride was used instead of dimethylamine-tetrahydrofuran solutionto give the title compound as a colorless solid (121 mg, yield 46%).

Reference Synthetic Example^(a) 139 tert-Butyl3-(cyanomethylene)azetidine-1-carboxylate

Potassium tert-butoxide (2.03 g, 21.1 mmol) in tetrahydrofuran (20 mL)was mixed with diethyl cyanomethylphosphonate (3.54 g, 20.0 mmol) intetrahydrofuran (20 mL) under cooling with ice and stirred for 30minutes. The reaction mixture was mixed with tert-butyl3-oxoazetidine-1-carboxylate (2.96 g, 17.3 mmol) obtained in ReferenceSynthetic Example^(a) 112 in tetrahydrofuran (20 mL) under cooling withice and then stirred at room temperature for 1 day. After addition ofwater, the reaction mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated sodium chloride, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=3/1 (v/v)) to give the title compound as a colorless solid (1.93g, yield 58%).

Reference Synthetic Example^(a) 1403-Hydroxy-N-methoxy-N-methyladamantane-1-carboxamide

3-Hydroxyadamantane-1-carboxylic acid (500 mg, 2.55 mmol) indichloromethane (15 mL) was mixed with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (587 mg,3.06 mmol), 1-hydroxybenzotriazole (103 mg, 0.765 mmol),N,O-dimethylhydroxylamine hydrochloride (298 mg, 3.06 mmol) andN,N-diisopropylethylamine (1.06 mL, 6.12 mmol) and then stirred at 40°C. for 1 hours. The reaction mixture was stirred with4-dimethylaminopyridine (779 mg, 6.38 mmol) at 40° C. for 1 hours. Afteraddition of saturated aqueous ammonium chloride, the reaction mixturewas extracted with chloroform. The organic layer was washed with 1Mhydrochloric acid and saturated aqueous sodium chloride, dried overanhydrous sodium sulfate and concentrated under reduced pressure to givethe title compound as a yellow oil (248 mg, yield 41%).

Reference Synthetic Example^(a) 1413-Hydroxyadamantan-1-yl)(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone

Isopropylmagnesium chloride-tetrahydrofuran solution (2.0 M, 0.518 mL,1.035 mmol) was gradually added dropwise to4-iodo-7H-pyrrolo[2,3-d]pyrimidine (56.4 mg, 0.230 mmol) intetrahydrofuran (1 mL) cooled to −78° C., and the resulting reactionmixture was stirred at −78° C. for 15 minutes. The reaction mixture wasmixed with (2,6-dimethylphenyl)magnesium bromide-tetrahydrofuransolution (1.0 M, 0.575 mL, 0.575 mmol) and3-hydroxy-N-methoxy-N-methyladamantane-1-carboxamide (55.1 mg, 0.23mmol) in tetrahydrofuran (1 mL) and then stirred at room temperature for1 day. After addition of saturated aqueous ammonium chloride, thereaction mixture was extracted with ethyl acetate. The organic layer waswashed with water and saturated aqueous sodium chloride, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel thin layer chromatography (ethylacetate) to give the title compound as a pale yellow solid (22.5 mg,yield 33%).

Synthetic Example^(a) 11-Cyclohexyl-3-methyl-7H-imidazo[1,5-c]pyrrolo[3,2-e]pyrimidine

Cyclohexyl[7-(triisopropylsilyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]methanone(48.2 mg, 0.120 mmol) obtained in Reference Synthetic Example^(a) 4 inacetic acid (1.2 mL) was stirred with ammonium acetate (46.2 mg, 0.600mmol) and acetaldehyde (purity 90%, 15 μl, 0.24 mmol) at 110° C. for 2.5hours, and the reaction mixture was allowed to cool to room temperature,basified with saturated aqueous sodium hydrogen carbonate and extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel thin layer chromatography (NH-PLC05 platemanufactured by Fuji Silysia Chemical Ltd.: ethyl acetate) and furtherpurified under the same conditions to give the title compound as a brownsolid (12.4 mg, yield 41%).

Synthetic Example^(a) 21-Cyclohexyl-7H-imidazo[1,5-c]pyrrolo[3,2-e]pyrimidine

Cyclohexyl[7-(triisopropylsilyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]methanone(52.5 mg, 0.136 mmol) obtained in Reference Synthetic Example^(a) 4 informamide (2 mL) was stirred with formic acid (0.4 mL) at 170° C. for 2hours. The reaction mixture was allowed to cool to room temperature, andafter dropwise addition of water, basified with 10 M aqueous sodiumhydroxide and extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was stirred with phosphorus oxychloride (2 mL) at 110° C.for 4 hours. The reaction mixture was allowed to cool to roomtemperature, and after dropwise addition of water, basified with 10 Maqueous sodium hydroxide and extracted with ethyl acetate. The organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (Hi Flash column amino type manufactured by YamazenCorporation: chloroform/methanol=7/1 (v/v)) and further purified bysilica gel thin layer chromatography (NH-PLC05 plate manufactured byFuji Silysia Chemical Ltd.: ethyl acetate) to give the title compound asa brown solid (2.29 mg. yield 7%).

Synthetic Example^(a) 3 Benzyl3-(7H-imidazo[1,5-c]pyrrolo[3,2-e]pyrimidin-1-yl)piperidine-1-carboxylate

Benzyl3-(7{[-2-(trimethylsilyl)ethoxy]methyl}-7H-imidazo[1,5-c]pyrrolo[3,2-e]pyrimidin-1-yl)piperidine-1-carboxylateobtained in Reference Synthetic Example^(a) 20 in dichloromethane (1 mL)was stirred with trifluoroacetic acid (0.5 mL) at room temperature for1.5 hours. The reaction mixture was concentrated under reduced pressureand azeotropically distilled with toluene. The resulting residue wasdissolved in a mixture of dichloromethane (1 mL) and methanol (0.5 mL)and stirred with ethylenediamine (50 μL, 0.75 mmol) and 1 M aqueoussodium hydroxide (0.5 mL, 0.5 mmol) at room temperature for one day. Thereaction mixture was diluted with ethyl acetate and washed withsaturated aqueous ammonium chloride and saturated aqueous sodiumchloride, and the organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (Hi Flash column amino typemanufactured by Yamazen Corporation: chloroform/methanol=10/1-p 5/1(v/v)) to give the title compound as a pale yellow oil (17.3 mg, yield52%).

Synthetic Example^(a) 43-[3-(7H-Imidazo[1,5-c]pyrrolo[3,2-e]pyrimidin-1-yl)piperidin-1-yl]-3-oxopropanenitrile

Benzyl3-(7H-imidazo[1,5-c]pyrrolo[3,2-e]pyrimidin-1-yl)piperidine-1-carboxylate(13.3 mg, 0.0354 mmol) and 10% palladium hydroxide-carbon (small amount)in ethanol (1.5 mL) was stirred at room temperature for 2.5 hours undera hydrogen atmosphere. The reaction mixture was filtered, and thefiltrate was concentrated under reduced pressure. The resulting residuewas dissolved in N,N-dimethylformamide (1 mL) and stirred with2-cyanoacetic acid (5.0 mg, 0.054 mmol),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (27.5 mg, 0.0722 mmol) and N,N-diisopropylethylamine(19.0 μL, 0.11 mmol) at room temperature for one day. After addition ofwater, the reaction mixture was extracted with ethyl acetate, and theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel thinlayer chromatography (NH-PLC05 plate manufactured by Fuji SilysiaChemical Ltd.: chloroform/methanol=15/1 (v/v)) to give the titlecompound as a pale yellow oil (1.02 mg, yield 11%).

Synthetic Example^(a) 51-o-Tolyl-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)(o-tolyl)methanone (50.0 mg, 0.211mmol) obtained in Reference Synthetic Example^(a) 10 in methanol (1 ml)was stirred with hydrazine monohydrate (295 μL, 9.48 mmol) at 75° C. for7 hours. After addition of water and 1 M aqueous sodium hydroxide, thereaction mixture was extracted with chloroform, and the organic layerwas dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The resulting residue (pale yellow amorphous, 60.3 mg)was dissolved in chloroform (4 mL) and stirred with manganese dioxide(91.6 mg, 1.05 mmol) at 75° C. for 6 hours. The reaction mixture wasfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=4/1→1/1 (v/v)) to give the title compound as a white solid (21.5mg, yield 41%).

Synthetic Example^(a) 61-Cyclohexyl-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

The reactions in Synthetic Example^(a) 5 were carried out insubstantially the same manners except thatcyclohexyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone obtained inReference Synthetic Example^(a) 12 was used instead of(7H-pyrrolo[2,3-d]pyrimidin-4-yl)(o-tolyl)methanone to give the titlecompound as a pale yellow solid (76.6 mg, yield 73%).

Synthetic Example^(a) 71-(2-Methylcyclohexyl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

The reactions in Synthetic Example^(a) 5 were carried out insubstantially the same manners except that(2-methylcyclohexyl)(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone obtainedin Reference Synthetic Example^(a) 14 was used instead of(7H-pyrrolo[2,3-d]pyrimidin-4-yl)(o-tolyl)methanone to give the titlecompound as a pale yellow amorphous (16.9 mg, yield 32%).

Synthetic Example^(a) 81-Cyclohexyl-2H-imidazo[1,5-c]pyrrolo[3,2-e]pyrimidine-3(7H)-thione

Cyclohexyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone (50 mg, 0.22 mmol)obtained in Reference Synthetic Example^(a) 12 in methanol (1 mL) wasstirred with hydroxylamine (50 wt % aq., 735 μL, 12.0 mmol) at 75° C.for 6 hours. After addition of water and 1 M aqueous sodium hydroxide,the reaction mixture was extracted with chloroform, and the organiclayer was dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The resulting residue (colorless oil, 53.0 mg) wasdissolved in methanol (3 mL) and stirred with zinc (128 mg, 1.96 mmol)and acetic acid (37.5 μL, 0.654 mmol) at 75° C. for 7 hours, and thereaction mixture was filtered. Chloroform and saturated aqueous sodiumhydrogen carbonate were added to the filtrate, and the precipitate wasseparated by filtration. The filtrate was extracted with chloroform, andthe organic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The resulting residue (pale yellowoil, 23.7 mg) was dissolved in methanol (1 mL) and stirred with carbondisulfide (62.0 μL, 1.03 mmol) and triethylamine (43.0 μL, 0.309 mmol)at 75° C. for 2 hours. The reaction mixture was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography (Hi Flash column amino type manufactured by YamazenCorporation: chloroform/methanol=10/1 (v/v)) to give the title compoundas a yellow solid (22.6 mg, yield 38%).

Synthetic Example^(a) 91-Cyclohexyl-2H-imidazo[1,5-c]pyrrolo[3,2-e]pyrimidin-3(7H)-one

Cyclohexyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone (100 mg, 0.436mmol) obtained in Reference Synthetic Example^(a) 12 in methanol (2 mL)was stirred with hydroxylamine (50 wt % aq., 1.34 mL, 21.8 mmol) at 75°C. for 5 hours. After addition of water and 1 M aqueous sodiumhydroxide, the reaction mixture was extracted with chloroform. Theorganic layer was washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The resulting residue (colorless oil, 110 mg) was dissolved inmethanol (3 mL) and stirred with zinc (258 mg, 3.93 mmol) and aceticacid (75.0 μL, 1.31 mmol) at 70° C. for 7.5 hours, and the reactionmixture was filtered. Chloroform and saturated aqueous sodium hydrogencarbonate were added to the filtrate, and the precipitate was separatedby filtration. The filtrate was extracted with dichloromethane, and theorganic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The resulting residue (pale yellowamorphous, 57.5 mg) was dissolved in chloroform (1 mL) and stirred withtriphosgene (29.6 mg, 0.0999 mmol) at room temperature for 3 hours.After addition of methanol, the reaction mixture was purified by silicagel column chromatography (Hi Flash column amino type manufactured byYamazen Corporation: chloroform/methanol=10/1 (v/v)) to give the titlecompound as a yellow solid (6.0 mg, yield 5.4%).

Synthetic Example^(a) 10[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methanol

1-{trans-4-[(tert-Butyldiphenylsilyloxy)methyl]cyclohexyl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine(48.0 mg, 0.0942 mmol) obtained in Reference Synthetic Example^(a) 24 intetrahydrofuran (3 mL) was cooled with ice and stirred withtetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 104 μL,0.104 mmol) for 4 hours while the temperature was gradually raised toroom temperature. After addition of water, the reaction solution wasextracted with ethyl acetate, and the organic layer was washed withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (chloroform/methanol=10/1(v/v)) to give the title compound as a pale yellow solid (25.3 mg, yield99%).

Synthetic Example^(a) 11 tert-Butyl4-methyl-3-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidine-1-carboxylate

The reactions in Synthetic Example^(a) 5 were carried out insubstantially the same manners except that tert-butyl4-methyl-3-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)piperidine-1-carboxylateobtained in Reference Synthetic Example^(a) 27 was used instead of(7H-pyrrolo[2,3-d]pyrimidin-4-yl)(o-tolyl)methanone to give the titlecompound as a pale yellow solid (1.0 mg, yield 1.3%).

Synthetic Example^(a) 123-[4-Methyl-3-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidin-1-yl]-3-oxopropanenitrile

tert-Butyl4-methyl-3-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidine-1-carboxylate(5.6 mg, 0.016 mmol) in 4 M hydrogen chloride-1,4-dioxane solution (1.0mL) was stirred under cooling with ice for 1 hour and concentrated underreduced pressure. The residue was dissolved in N,N-dimethylformamide (1mL) and mixed with 2-cyanoacetic acid (2.7 mg, 0.0314 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N,′N′-tetramethyluroniumhexafluorophosphate (11.9 mg, 0.0314 mmol) and then withN,N-diisopylethylamine (0.0082 mL, 0.0471 mmol) and stirred at roomtemperature for 2 hours. After addition of water, the reaction mixturewas extracted with ethyl acetate, and the organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel thin layer chromatography (NH-PLC05plate manufactured by Fuji Silysia Chemical Ltd.:chloroform/methanol=15/1 (v/v)) and further purified by silica gel thinlayer chromatography (ethyl acetate) to give the title compound as apale yellow solid (0.62 mg, yield 12%).

Synthetic Example^(a) 13 tert-Butyl3-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidine-1-carboxylate

The reactions in Synthetic Example^(a) 5 were carried out insubstantially the same manners except that tert-butyl3-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)piperidine-1-carboxylateobtained in Reference Synthetic Example^(a) 29 was used instead of(7H-pyrrolo[2,3-d]pyrimidin-4-yl)(o-tolyl)methanone to give the titlecompound as a pale yellow oil (48.2 mg, yield 47%).

Synthetic Example^(a) 14 Benzyl3-(7H-pyrrolo[3,2-e][1,2,3]triazolo[,1,5-c]pyrimidin-1-yl)piperidine-1-carboxylate

The reactions in Synthetic Example^(a) 5 were carried out insubstantially the same manners except that benzyl3-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)piperidine-1-carboxylateobtained in Reference Synthetic Example^(a) 32 was used instead of(7H-pyrrolo[2,3-d]pyrimidin-4-yl)(o-tolyl)methanone to give the titlecompound as a pale yellow solid (185 mg, yield 85%).

Synthetic Example^(a) 151-(Piperidin-3-yl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

Benzyl3-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidine-1-carboxylate(25.0 mg, 0.0664 mmol) in ethanol was stirred with 5% palladium-carbon(10 mg) under a hydrogen atmosphere at 50° C. for 2.5 hours. Thereaction mixture was filtered, and the filtrate was concentrated underreduced pressure to give the title compound as a light brown solid (16.1mg, yield quantitative).

Synthetic Example^(a) 161-(1-Benzylpiperidin-3-yl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

The reactions in Synthetic Example^(a) 5 were carried out insubstantially the same manners except that(1-benzylpiperidin-3-yl)(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanoneobtained in Reference Synthetic Example^(a) 35 was used instead of(7H-pyrrolo[2,3-d]pyrimidin-4-yl)(o-tolyl)methanone to give the titlecompound as a pale yellow solid (2.6 mg, yield 2.5%).

Synthetic Example^(a) 171-[3-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidin-1-yl]-3,3,3-trifluoropropan-1-one

1-(Piperidin-3-yl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine(20.0 mg., 0.0825 mmol) obtained in Synthetic Example^(a) 15 inN,N-dimethylformamide (1.5 mL) was mixed with 3,3,3-trifluoropropanoicacid (8.6 μL, 0.099 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (62.7 mg, 0.165 mmol) and then withN,N-diisopropylethylamine (0.0431 ml, 0.248 mmol) and stirred at roomtemperature for one day. After addition of water, the reaction mixturewas extracted with ethyl acetate, and the organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=1/1→1/2 (v/v)→ethyl acetate) to give the title compound as acolorless solid (7.3 mg, yield 25%).

Synthetic Example^(a) 181-[1-(Pyridin-3-ylmethyl)piperidin-3-yl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

1-(Piperidin-3-yl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine(21.9 mg, 0.0903 mmol) obtained in Synthetic Example^(a) 15 in methanol(1.5 mL) was stirred with 3-pyridinecarboxyaldehyde (12.7 μL, 0.135mmol) at 50° C. for 1.5 hours, then with a small amount of acetic acidat room temperature for 2 hours and with sodium triacetoxyborohydride(28.6 mg, 0.135 mmol) at room temperature for one day. After addition ofwater, the reaction mixture was extracted with chloroform, and theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (Hi Flash column amino type manufactured by YamazenCorporation: chloroform/methanol=15/1 (v/v)) and then by silica gel thinlayer chromatography (NH-PLC05 plate manufactured by Fuji SilysiaChemical Ltd.: ethyl acetate) to give the title compound as a colorlesssolid (5.8 mg, yield 19%).

Synthetic Example^(a) 195-{[3-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)-piperidin-1-yl]methyl}thiazole

The reactions in Synthetic Example^(a) 18 were carried out insubstantially the same manners except that thiazole-5-carbaldehyde wasused instead of 3-pyridinecarboxyaldehyde to give the title compound asa colorless solid (3.4 mg, yield 12%).

Synthetic Example^(a) 203-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)-N-(1,3,4-thiadiazol-2-yl)Piperidine-1-carboxamide

1-(Piperidin-3-yl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine(22.1 mg, 0.0912 mmol) obtained in Synthetic Example^(a) 15 intetrahydrofuran (1.5 mL) was stirred with phenyl1,3,4-thiadiazol-2-ylcarbamate (24.1 mg, 0.109 mmol) obtained inReference Synthetic Example^(a) 36 and triethylamine (0.0191 mg, 0.137mmol) at 60° C. for 1.5 hours and then stirred at room temperature forone day. The precipitate in the reaction mixture was washed with ethylacetate, methanol and tetrahydrofuran, and the solid was dried underreduced pressure to give the title compound as a light brown solid (2.4mg, yield 7%).

Synthetic Example^(a) 21N-(3-Methylisothiazol-5-yl)-3-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)Piperidine-1-carboxamide

1-(Piperidin-3-yl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine(23.2 mg., 0.0957 mmol) obtained in Synthetic Example^(a) 15 intetrahydrofuran (1.5 mL) was stirred with phenyl(3-methylisothiazol-5-yl)carbamate (26.9 mg, 0.115 mmol) obtained inReference Synthetic Example^(a) 37 and triethylamine (0.0201 mL, 0.144mmol) at 60° C. for 1.5 hours. After addition of water, the reactionmixture was extracted with ethyl acetate, and the organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(Hi Flash column amino type manufactured by Yamazen Corporation:chloroform/methanol=7/1 (v/v)), and the resulting solid was washed withethyl acetate, methanol and tetrahydrofuran to give the title compoundas a light brown solid (3.0 mg, yield 8.3%).

Synthetic Example^(a) 224-{[3-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidin-1-yl]methyl}benzonitrile

1-(Piperidin-3-yl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine(29.4 mg., 0.121 mmol) obtained in Synthetic Example^(a) 15 inacetonitrile (1.5 mL) was stirred with 4-(bromomethyl)benzonitrile (31.0mg, 0.168 mmol) and N,N-diisopropylethylamine (0.0317 mL, 0.182 mmol) at60° C. for 2 hours. The reaction mixture was purified by silica gelcolumn chromatography (Hi Flash column amino type manufactured byYamazen Corporation: hexane/ethyl acetate=1/1 (v/v)→ethyl acetate) togive the title compound as a colorless solid (24.9 mg, yield 58%).

Synthetic Example^(a) 231-{1-[4-(Trifluoromethyl)benzyl]piperidin-3-yl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

The reactions in Synthetic Example^(a) 22 were carried out insubstantially the same manners except that1-(bromomethyl)-4-(trifluoromethyl)benzene was used instead of4-(bromomethyl)benzonitrile to give the title compound as a light brownsolid (30.9 mg, yield 68%).

Synthetic Example^(a) 24 tert-Butyl4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidine-1-carboxylate

The reactions in Synthetic Example^(a) 5 were carried out insubstantially the same manners except that tert-butyl4-(7H-pyrrolo[2,3-d]pyrimidin-4-carbonyl)piperidine-1-carboxylateobtained in Reference Synthetic Example^(a) 39 was used instead of(7H-pyrrolo[2,3-d]pyrimidin-4-yl)(o-tolyl)methanone to give the titlecompound as a pale yellow solid (157 mg, yield 69%).

Synthetic Example^(a) 251-[1-(2,2,2-Trifluoroethyl)piperidin-4-yl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

The reactions in Synthetic Example^(a) 5 were carried out insubstantially the same manners except that(7H-pyrrolo[2,3-d]pyrimidin-4-yl)[1-(2,2,2-trifluoroethyl)piperidin-4-yl]methanoneobtained in Reference Synthetic Example^(a) 42 was used instead of(7H-pyrrolo[2,3-d]pyrimidin-4-yl)(o-tolyl)methanone to give the titlecompound as a pale yellow solid (6.6 mg, yield 12%).

Synthetic Example^(a) 26 Benzyl4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[,1,5-c]pyrimidin-1-yl)piperidine-1-carboxylate

The reactions in Synthetic Example^(a) 5 were carried out insubstantially the same manners except that benzyl4-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)piperidine-1-carboxylateobtained in Reference Synthetic Example^(a) 44 was used instead of(7H-pyrrolo[2,3-d]pyrimidin-4-yl)(o-tolyl)methanone to give the titlecompound as a colorless solid (49.6 mg, yield 34%).

Synthetic Example^(a) 271-(Piperidin-4-yl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

5% Palladium-carbon (10.0 mg) was added to benzyl4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidine-1-carboxylate(30.0 mg, 0.0800 mmol) in methanol (2 mL) under an argon atmosphere, andafter the reaction system was flushed with hydrogen, the reactionmixture was stirred at room temperature for 6 hours and then filtered.The filtrate was concentrated under reduced pressure. The resultingyellow solid was washed with methanol and collected by filtration togive the title compound as a pale yellow solid (5.0 mg, yield 26%).

Synthetic Example^(a) 281-[1-(Pyridin-3-ylmethyl)piperidin-4-yl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

1-(Piperidin-4-yl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine(11.0 mg, 0.0450 mmol) in a mixture of methanol (1 mL) andtetrahydrofuran (1 mL) was stirred with 3-pyridinecarboxyaldehyde (5.0μL, 0.054 mmol), acetic acid (33 μL) and sodium cyanoborohydride (4.3mg, 0.068 mmol) at room temperature for one day. The reaction mixturewas stirred with sodium triacetoxyborohydride (10.0 mg, 0.047 mmol) foranother 2 hours. The resulting reaction mixture was purified by silicagel thin layer chromatography (methanol/chloroform=1/9 (v/v)) twice togive the title compound as a colorless solid (1.4 mg, yield 9.3%).

Synthetic Example^(a) 291-[4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidin-1-yl]-3,3,3-trifluoropropan-1-one

1-(Piperidin-4-yl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidineacetate (30.0 mg, 0.0992 mmol) obtained in Reference SyntheticExample^(a) 104 in N,N-dimethylformamide (1 mL) was stirred with3,3,3-trifluoropropionic acid (14.0 μL, 0.161 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (48.0 mg,0.248 mmol), 1-hydroxybenzotriazole (34.0 mg, 0.248 mmol) andtriethylamine (43.0 μL, 0.310 mmol) at room temperature for 3 hours andthen with water (1 mL) for another 1 day. After addition of water, thereaction mixture was extracted with ethyl acetate, and the organic layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate=2/1 (v/v)) to give the title compound as acolorless solid (11.7 mg, yield 34%).

Synthetic Example^(a) 304-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)-N-(1,3,4-thiadiazol-2-yl)piperidine-1-carboxamide

1-(Piperidin-4-yl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidineacetate (25.0 mg, 0.0827 mmol) obtained in Reference SyntheticExample^(a) 104 in tetrahydrofuran (1 mL) was stirred with phenyl1,3,4-thiadiazol-2-ylcarbamate (27.0 mg, 0.124 mmol) obtained inReference Synthetic Example^(a) 36 and triethylamine (22.0 μL, 0.155mmol) at room temperature for 2 hours. Water and ethyl acetate wereadded to the reaction mixture, and the insolubles were collected byfiltration. The resulting solid was washed with methanol, chloroform,acetonitrile and ethanol to give the title compound as a colorless solid(19.3 mg, yield 63%).

Synthetic Example^(a) 31N-(3-Methylisothiazol-5-yl)-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)Piperidine-1-carboxamide

The reactions Synthetic Example^(a) 30 were carried out in substantiallythe same manners except that phenyl (3-methylisothiazol-5-yl)carbamateobtained in Reference Synthetic Example^(a) 37 was used instead ofphenyl 1,3,4-thiadiazol-2-ylcarbamate to give the title compound as apale yellow solid (17.6 mg, yield 56%).

Synthetic Example^(a) 321-(1-Benzylpiperidin-4-yl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

1-(Piperidin-4-yl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidineacetate (20.0 mg, 0.0662 mmol) obtained in Reference SyntheticExample^(a) 104 in acetonitrile (1 mL) was stirred with benzyl bromide(15.0 μL, 0.124 mmol) and N,N-diisopropylethylamine (28.0 μL, 0.166mmol) at 60° C. for 2 hours. The reaction mixture was purified by silicagel column chromatography (methanol/chloroform=1/30→1/25 (v/v)), and theresulting solid was washed with isopropyl ether to give the titlecompound as a colorless solid (2.92 mg, yield 13%).

Synthetic Examples^(a) 33 to 43

The reactions in Synthetic Example^(a) 32 were carried out insubstantially the same manners except that 4-(trifluoromethyl)benzylbromide, 4-cyanobenzyl bromide, 3-cyanobenzyl bromide,4-(chloromethyl)-3,5-dimethylisoxazole, 4-(trifluoromethoxy)benzylbromide, 4-(trifluoromethylthio)benzyl bromide,3-(trifluoromethyl)benzyl bromide, 4-(bromomethyl)-3-fluorobenzonitrile,1-bromo-4-(bromomethyl)benzene,1-(2-bromoethyl)-4-(trifluoromethyl)benzene or 4-fluorobenzyl bromidewas used instead of benzyl bromide to give the compounds of SyntheticExamples^(a) 33 to 43. The names, morphologies and yields of thesynthesized compounds are shown in Table^(a) 7.

TABLE^(a) 7 Ex Compound Name Morphology Yield 331-{1-[4-(trifluoromethyl)benzyl]piperidin- colorless solid 64%4-yl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine 344-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, pale yellow 38%5-c]pyrimidin-1-yl)piperidin-1-yl]methyl)} benzonitrile solid 353-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 37%5-c]pyrimidin-1-yl)piperidin-1-yl]methyl} benzonitrile 364-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 38%5-c]pyrimidin-1-yl)piperidin-1-yl]methyl}- 3,5-dimethylisoxazole 371-{1-[4-(trifluoromethoxy)benzyl]piperidin- colorless solid 33%4-yl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine 381-(1-{4-[(trifluoromethyl)thio]benzyl}piperidin- colorless solid 28%4-yl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine 391-{1-[3-(trifluoromethyl)benzyl]piperidin- colorless solid 35%4-yl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine 404-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 45%5-c]pyrimidin-1-yl) piperidin-1-yl]methyl}- 3-fluorobenzonitrile 411-[1-(4-bromobenzyl)piperidin-4-yl]-7H- colorless solid 64% pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine 421-{1-[4-(trifluoromethyl)phenethyl]piperidin- colorless solid 33%4-yl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine hydrochloride43 1-[1-(4-fluorobenzyl)piperidin-4-yl]-7H- colorless solid 2.0% pyrrolo [3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

Synthetic Example^(a) 445-{[4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidin-1-yl]methyl}thiazole

1-(Piperidin-4-yl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidineacetate (20.0 mg, 0.0662 mmol) obtained in Reference SyntheticExample^(a) 104 in methanol (1 mL) was stirred withthiazole-5-carbaldehyde (11.0 μL, 0.124 mmol), acetic acid (100 μL) and2-picoline borane (13.0 mg, 0.124 mmol) at room temperature for one day.The reaction mixture was purified by silica gel column chromatography(methanol/chloroform=1/30>1/25→1/20 (v/v)). The resulting solid waswashed with isopropyl ether to give the title compound as a colorlesssolid (9.05 mg, yield 40%).

Synthetic Examples^(a) 45 to 55

The reactions in Synthetic Example 44 were carried out in substantiallythe same manners except that 3-phenylpropionaldehyde,3-fluoro-4-methoxybenzaldehyde, 3,5-bis(trifluoromethyl)benzaldehyde,2-formylthiazole, 5-chlorothiophene-2-carboxaldehyde,cyclohexanecarboxaldehyde, cyclopentanone,6-(trifluoromethyl)-3-pyridinecarboxaldehyde,3,5-difluoro-4-formylbenzonitrile, 4-chlorobenzaldehyde or3-fluorobenzaldehyde was used instead of thiazole-5-carbaldehyde to givethe compounds of Synthetic Examples^(a) 45 to 55. The names,morphologies and yields of the compounds synthesized are shown inTable^(a) 8.

TABLE^(a) 8 Ex Compound Name Morphology Yield 451-[1-(3-phenylpropyl)piperidin-4-yl]-7H- colorless solid 35%pyrrolo[3,2-e][1,2,3]triazolo[1,5- c]pyrimidine 461-[1-(3-fluoro-4-methoxybenzyl)piperidin- colorless solid 62%4-yl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine 47 1-{1-[3,5-colorless solid 31% bis(trifluoromethyl)benzyl]piperidin-4-yl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine 482-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 61%5-c]pyrimidin-1-yl)piperidin-1- yl]methyl}thiazole 491-{1-[(5-chlorothiophen-2- colorless solid 27%yl)methyl]piperidin-4-yl}-7H-pyrrolo[3,2- e][1,2,3]triazolo[1,5-c]pyrimidine 50 1-[1-(cyclohexylmethyl)piperidin-4-yl]- colorlesssolid 41% 7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5- c]pyrimidine 511-(1-cyclopentylpiperidin-4-yl)-7H- colorless solid 63%pyrrolo[3,2-e][1,2,3]triazolo[1,5- c]pyrimidine 521-(1-{[6-(trifluoromethyl)pyridin-3- colorless solid 55%yl]methyl}piperidin-4-yl)-7H-pyrrolo[3,2- e][1,2,3]triazolo[1,5-c]pyrimidine 534-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 5.0% 5-c]pyrimidin-1-yl)piperidin-1-yl]methyl}- 3,5-difluorobenzonitrile 541-[1-(4-chlorobenzyl)piperidin-4-yl]-7H- colorless solid 24%pyrrolo[3,2-e][1,2,3]triazolo[1,5- c]pyrimidine 551-[1-(3-fluorobenzyl)piperidin-4-yl]-7H- colorless solid 33%pyrrolo[3,2-e][1,2,3]triazolo[1,5- c]pyrimidine

Synthetic Example^(a) 561-{1-[4-(Trifluoromethyl)cyclohexyl]piperidin-4-yl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

The reactions in Synthetic Example^(a) 44 were carried out insubstantially the same manners except that4-(trifluoromethyl)cyclohexanone was used instead ofthiazole-5-carbaldehyde to give an isomer mixture as a pale yellowsolid. The isomer mixture was purified by silica gel thin layerchromatography (methanol/chloroform=1/9 (v/v)) to give the two isomersof the title compound in a less polar fraction (Synthetic Example^(a)56a; pale yellow solid, 5.6 mg, yield 22%) and in a more polar fraction(Synthetic Example^(a) 56b; pale yellow solid, 4.9 mg, yield 19%).

Synthetic Example^(a) 574-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)-N-[3-(trifluoromethyl)phenyl]piperidine-1-carboxamide

1-(Piperidin-4-yl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidineacetate (20.0 mg, 0.0662 mmol) obtained in Reference SyntheticExample^(a) 104 in tetrahydrofuran (1 mL) was stirred with3-(trifluoromethyl)phenyl isocyanate (14.0 μL, 0.0990 mmol) andtriethylamine (14.0 μL, 0.0990 mmol) at room temperature for 3 days. Thereaction mixture was purified by silica gel thin layer chromatography(methanol/chloroform=1/9 (v/v)) to give the title compound as a lightgray solid (7.5 mg, yield 27%).

Synthetic Example^(a) 58[4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[,1,5-c]pyrimidin-1-yl)piperidin-1-yl][4-(trifluoromethyl)phenyl]methanone

1-(Piperidin-4-yl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidineacetate (20.0 mg, 0.0662 mmol) obtained in Reference SyntheticExample^(a) 104 in N,N-dimethylformamide (1 mL) was stirred with4-(trifluoromethyl)benzoyl chloride (14.8 μL, 0.100 mmol) andtriethylamine (13.9 μL, 0.100 mmol) under cooling with ice for 80minutes. After addition of water, the reaction mixture was extractedwith chloroform, and the organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel thin layer chromatography(methanol/chloroform=1/19 (v/v)) to give the title compound as acolorless oil (16.3 mg, yield 59%)_(.)

Synthetic Example^(a) 59tert-Butyl[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]carbamate

The reactions in Synthetic Example^(a) 5 were carried out insubstantially the same manners except thattert-butyl[trans-4-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)cyclohexyl]carbamateobtained in Reference Synthetic Example^(a) 46 was used instead of(7H-pyrrolo[2,3-d]pyrimidin-4-yl)(o-tolyl)methanone to give the titlecompound as a colorless solid (4.7 mg, yield 15%).

Synthetic Example^(a) 60Benzyl[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]carbamate

The reactions in Synthetic Example^(a) 5 were carried out insubstantially the same manners except thatbenzyl[trans-4-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)cyclohexyl]carbamateobtained in Reference Synthetic Example^(a) 48 was used instead of(7H-pyrrolo[2,3-d]pyrimidin-4-yl)(o-tolyl)methanone to give the titlecompound as a colorless solid (10.0 mg, yield 29%).

Synthetic Example^(a) 61trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[,1,5-c]pyrimidin-1-yl)cyclohexanamine

5% Palladium-carbon (5.00 mg) was added tobenzyl[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]carbamate(7.00 mg, 0.0180 mmol) in a mixture of ethanol (1 mL) and chloroform (1mL) under an argon atmosphere, and after the reaction system was flushedwith hydrogen, the reaction mixture was stirred at room temperature forone day and then filtered. The filtrate was concentrated under reducedpressure. The resulting residue was purified by silica gel thin layerchromatography (NH-PLC05 plate manufactured by Fuji Silysia ChemicalLtd.:methanol/chloroform=1/19 (v/v)) to give the title compound as acolorless solid (0.35 mg, yield 8.0%).

Synthetic Example^(a) 621-[trans-4-(Methoxymethyl)cyclohexyl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

The reactions in Synthetic Example^(a) 5 were carried out insubstantially the same manners except that[trans-4-(methoxymethyl)cyclohexyl](7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanoneobtained in Reference Synthetic Example^(a) 50 was used instead of(7H-pyrrolo[2,3-d]pyrimidin-4-yl)(o-tolyl)methanone to give the titlecompound as a colorless solid (52.4 mg, yield 63%).

Synthetic Example^(a) 631-[trans-4-Methoxycyclohexyl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

The reactions in Synthetic Example^(a) 5 were carried out insubstantially the same manners except that(trans-4-methoxycyclohexyl)(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanoneobtained in Reference Synthetic Example^(a) 53 was used instead of(7H-pyrrolo[2,3-d]pyrimidin-4-yl)(o-tolyl)methanone to give the titlecompound as a pale yellow solid (7.80 mg, yield 7.6%).

Synthetic Examples^(a) 64 to 69

The reactions in Synthetic Example^(a) 5 were carried out insubstantially the same manners except that the compounds obtained inReference Synthetic Examples^(a) 61 to 66 were used instead of(7H-pyrrolo[2,3-d]pyrimidin-4-yl)(o-tolyl)methanone to give the titlecompounds of Synthetic Examples^(a) 64 to 69. The names, morphologiesand yields of the compounds synthesized are shown in Table^(a) 9.

TABLE^(a) 9 Ex Compound Name Morphology Yield 641-(4,4-difluorocyclohexyl)-7H-pyrrolo[3, pale cream 51%2-e][1,2,3]triazolo[1,5-c]pyrimidine solid 651-(bicyclo[2.2.1]heptan-2-yl)-7H-pyrrol[3, colorless solid 47%2-e][1,2,3]triazolo[1,5-e]pyrimidine 66 1-cycloheptyl-7H-1- colorlesssolid 49% pyrrolo[3,2-e][1,2,3]triazolo[1,5- c]pyrimidine 671-cyclobutyl-7H-pyrrolo[3,2- colorless solid 56%e][1,2,3]triazolo[1,5-c]pyrimidine 68 1-cyclopentyl-7H-pyrrolo[3,2-yellow 10% e][1,2,3]triazolo[1,5-c]pyrimidine amorphous 691-[trans-4-(trifluoromethyl)cyclohexyl]- colorless solid 12%7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5- c]pyrimidine

Synthetic Example^(a) 701-[trans-4-(Trifluoromethyl)cyclohexyl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

The reactions in Synthetic Example^(a) 5 were carried out insubstantially the same manners except that(7H-pyrrolo[2,3-d]pyrimidin-4-yl)[cis-4-(trifluoromethyl)cyclohexyl]methanoneobtained in Reference Synthetic Example^(a) 67 was used instead of(7H-pyrrolo[2,3-d]pyrimidin-4-yl)(o-tolyl)methanone to give the titlecompound as a colorless solid (12.0 mg, yield 23%). (although thecis-isomer was used as the starting material, only the trans-isomer ofthe title compound was obtained.)

Synthetic Example^(a) 71S-{[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}ethanethioate

Triphenylphosphine (58.0 mg, 0.221 mmol) in tetrahydrofuran (1 mL) wasmixed with diisopropyl azodicarboxylate (116 μL, 0.428 mmol) and[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methanol(30.0 mg, 0.111 mmol) obtained in Synthetic Example^(a) 10 andthioacetic acid (16.0 μL, 0.225 mmol) under cooling with ice, andstirred for 30 minutes while the temperature was gradually raised toroom temperature. After addition of water, the reaction mixture wasextracted with ethyl acetate, and the organic layer was washed withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethylacetate/hexane=1/10→1/3 (v/v)) to give the title compound as a colorlesssolid (22.4 mg, yield 62%).

Synthetic Example^(a) 72[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methylacetate

The reactions in Synthetic Example^(a) 71 were carried out insubstantially the same manners except that acetic acid was used insteadof thioacetic acid to give the title compound as a colorless solid (18.3mg, yield 53%).

Synthetic Example^(a) 731-[trans-4-(Fluoromethyl)cyclohexyl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methanol(30.0 mg, 0.111 mmol) obtained in Synthetic Example^(a) 10 suspended indichloromethane (3 mL) was mixed with N,N-diethylaminosulfur trifluoride(16.1 μL, 0.122 mmol) under cooling with ice and stirred for 30 minuteswhile the temperature was gradually raised to room temperature. Afteraddition of water, the reaction mixture was extracted with ethylacetate, and the organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane=1/5→1/3 (v/v)) to give the titlecompound as a colorless solid (6.7 mg, yield 22%).

Synthetic Example^(a) 741-[trans-4-(Bromomethyl)cyclohexyl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methanol(50.0 mg, 0.184 mmol) obtained in Synthetic Example^(a) 10 indichloromethane (3 mL) was mixed with triphenylphosphine (58.0 mg, 0.221mmol) and N-bromosuccinimide (39.0 mg, 0.221 mmol) under cooling withice and stirred for 19 hours while the temperature was gradually raisedto room temperature. The reaction mixture was purified by silica gelcolumn chromatography (ethyl acetate/hexane=1/1 (v/v)) to give the titlecompound as a colorless solid (27.4 mg, yield 44%).

Synthetic Example^(a) 751-[trans-4-(Chloromethyl)cyclohexyl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

The reactions in Synthetic Example^(a) 74 were carried out insubstantially the same manners except that N-chlorosuccinimide was usedinstead of N-bromosuccinimide to give the title compound as a colorlesssolid (1.25 mg, yield 2%).

Synthetic Example^(a) 76[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methanethiol

S-{[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}ethanethioate(30.0 mg, 0.0911 mmol) obtained in Synthetic Example^(a) 71 in methanol(2 mL) was stirred with sodium methoxide (28 wt % solution in methanol,10 μL) at room temperature for 30 minutes. The solid precipitated in thereaction solution was removed by filtration and washed with methanol.The filtrate and the washings were mixed with water, and theprecipitated solid was collected by filtration and dried under reducedpressure to give the title compound as a colorless solid (12.9 mg, yield49%).

Synthetic Example^(a) 771-{trans-4-[(Methylsulfonyl)methyl]cyclohexyl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

1-[trans-4-(Bromomethyl)cyclohexyl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine(27.3 mg, 0.0817 mmol) obtained in Synthetic Example^(a) 74 inN,N-dimethylformamide (2 mL) was stirred with sodium methanesulfinate(10.8 mg, 0.106 mmol) at room temperature for 30 minutes and then at 65°C. for 1.5 hours. The reaction mixture was allowed to cool to roomtemperature and stirred with sodium methanesulfinate (21.7 mg, 0.212mmol) at 65° C. for 7.5 hours. After addition of water, the reactionmixture was extracted with ethyl acetate, and the organic layer waswashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residueswas purified by silica gel column chromatography (ethylacetate/hexane=1/1 (v/v)) to give the title compound as a colorlesssolid (5.3 mg, yield 25%).

Synthetic Example^(a) 78trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanecarbaldehyde

[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methanol(50.0 mg, 0.184 mmol) obtained in Synthetic Example^(a) 10 in a mixtureof toluene (1 mL) and dimethyl sulfoxide (200 μL) was stirred with2-iodoxybenzoic acid (62.0 mg, 0.221 mmol) at room temperature for 30minutes and at 50° C. for 3 hours. After addition of saturated aqueoussodium hydrogen carbonate, the reaction mixture was extracted with ethylacetate. The organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residues was purified by silica gel columnchromatography (ethyl acetate/hexane=1/1 (v/v)) to give the titlecompound as a colorless solid (38.0 mg, yield 77%).

Synthetic Example^(a) 791-(trans-4-(Difluoromethyl)cyclohexyl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

The reactions in Synthetic Example^(a) 73 were carried out insubstantially the same manners except thattrans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanecarbaldehydewas used instead of[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methanolto give the title compound as a colorless solid (21.1 mg, yield 65%).

Synthetic Example^(a) 80trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanecarboxylicacid

trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanecarbaldehyde(25.8 mg, 0.0958 mmol) obtained in Synthetic Example′ 78 in t-butanol(0.31 mL) was mixed with sodium dihydrogen phosphate (34.4 mg, 0.287mmol), water (0.31 mL) and 2-methyl-2-butene (0.31 mL, 2.87 mmol) andthen with sodium chlorite (43.3 mg, 0.479 mmol) and stirred at roomtemperature for 2 hours. After addition of saturated aqueous sodiumthiosulfate, the reaction mixture was extracted with ethyl acetate, andthe organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (chloroform/methanol=10/1→4/1→2/1 (v/v)) togive the title compound as a colorless solid (14.7 mg, yield 54%).

Synthetic Example^(a) 81trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanol

1-{4-[(tert-Butyldiphenylsilyl)oxy]cyclohexyl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine(400 mg, 0.807 mmol) obtained in Reference Synthetic Example^(a) 70 intetrahydrofuran (8 mL) was mixed with tetrabutylammonium fluoride (1 Msolution in tetrahydrofuran, 0.97 mL, 0.986 mmol) under cooling with iceand stirred at room temperature for 2 hours and then at 40° C. for 1.5hours. The reaction solution was stirred with tetrabutylammoniumfluoride (1 M solution in tetrahydrofuran, 0.458 mL, 0.484 mmol) at 40°C. for 1 hour. After addition of water, the reaction solution wasextracted with chloroform, and the organic layer was washed withsaturated aqueous sodium chloride, dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate→chloroform/methanol=10/1(v/v)) to give the title compound as a colorless solid (78.1 mg, yield37%).

Synthetic Example^(a) 824-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanone

The reactions in Synthetic Example^(a) 78 were carried out insubstantially the same manners except thattrans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanolwas used instead of[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methanolto give the title compound as a pale yellow solid (27.1 mg, yield 35%).

Synthetic Example^(a) 83cis-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanol

1-{4-[(tert-Butyldimethylsilyl)oxy]cyclohexyl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine(1.18 g, 3.16 mmol) obtained in Reference Synthetic Example^(a) 74 intetrahydrofuran (10 mL) was stirred with tetrabutylammonium fluoride (1M solution in tetrahydrofuran, 3.8 mL, 3.79 mmol) at room temperaturefor 15 hours and then with tetrabutylammonium fluoride (1 M solution intetrahydrofuran, 7.6 mL, 7.58 mmol) at 60° C. for 8 hours and thenallowed to cool to room temperature. After addition of water, thereaction mixture was extracted with ethyl acetate, and the organic layerwas washed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethylacetate/hexane=1/1 (v/v)→ethyl acetate) to give a less polar fraction(colorless solid, 237 mg) and a more polar fraction (colorless solid,438 mg). The less polar fraction was stirred with tetrabutylammoniumfluoride (1 M solution in tetrahydrofuran, 440 μL) at room temperaturefor 4 days. After addition of water, the reaction solution was extractedwith ethyl acetate, and the organic layer was washed with saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The concentrate was purified bysilica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)→ethylacetate) to give the title compound as a colorless solid (66.4 mg, yield14%).

Synthetic Example^(a) 84 Benzyl4-(7H-imidazo[1,5-c]pyrrolo[3,2-e]pyrimidin-1-yl)piperidine-1-carboxylate

The reactions in Synthetic Example^(a) 3 were carried out insubstantially the same manners except that benzyl4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-imidazo[1,5-c]pyrrolo[3,2-e]pyrimidin-1-yl)piperidine-1-carboxylateobtained in Reference Synthetic Example^(a) 78 was used instead ofbenzyl3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-imidazo[1,5-c]pyrrolo[3,2-e]pyrimidin-1-yl)piperidine-1-carboxylateto give the title compound as a yellow solid (4.6 mg, yield 2%).

Synthetic Example^(a) 85 Benzyl4-(3-thioxo-3,7-dihydro-2H-imidazo[1,5-c]pyrrolo[3,2-e]pyrimidin-1-yl)piperidine-1-carboxylate

Benzyl4-[amino(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl]piperidine-1-carboxylate(50.0 mg, 0.137 mmol) obtained in Reference Synthetic Example^(a) 79 inmethanol (1 mL) was stirred with carbon disulfide (81.0 μL, 1.35 mmol)and triethylamine (56.0 μL, 0.405 mmol) at 75° C. for 1.5 hours. Thereaction mixture was allowed to cool to room temperature, and theprecipitated solid was collected by filtration and washed with methanolto give the title compound as a yellow solid (28.0 mg, yield 51%).

Synthetic Example^(a) 861-{1-[4-(Trifluoromethyl)benzyl]piperidin-4-yl}-2H-imidazo[1,5-c]pyrrolo[3,2-e]pyrimidine-3-(7H)-thione

The reactions in Synthetic Example^(a) 85 were carried out insubstantially the same manners except that(7H-pyrrolo[2,3-d]pyrimidin-4-yl){1-[4-(trifluoromethyl)benzyl]piperidin-4-yl}methanamineobtained in Reference Synthetic Example^(a) 82 was used instead ofbenzyl4-[amino(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl]piperidine-1-carboxylateto give the title compound as a yellow solid (2.6 mg, yield 4%).

Synthetic Example^(a) 87 Benzyl3-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)azetidine-1-carboxylate

The reactions in Synthetic Example^(a) 5 were carried out insubstantially the same manners except that benzyl3-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)azetidine-1-carboxylateobtained in Reference Synthetic Example^(a) 84 was used instead of(7H-pyrrolo[2,3-d]pyrimidin-4-yl)(o-tolyl)methanone to give the titlecompound as a yellow solid (186 mg, yield 60%).

Synthetic Example^(a) 884-{[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}thiomorpholine1,1-dioxide

trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanecarbaldehyde(30.0 mg, 0.111 mmol) obtained in Synthetic Example^(a) 78 in a mixtureof methanol (2 mL) and acetic acid (200 μL) was stirred withthiomorpholine 1,1-dioxide (22.6 mg, 0.167 mmol) at room temperature for1 hour, and then with 2-picoline borane (17.9 mg, 0.167 mmol) at roomtemperature for another 3 hours. After addition of water, the reactionmixture was extracted with ethyl acetate, and the organic layer waswashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. A mixture ofethyl acetate (1 mL), hexane (1 mL) and chloroform (100 μL) was added tothe residue, and the precipitated solid was collected by filtration togive the title compound as a colorless solid (28.3 mg, yield 65%).

Synthetic Examples^(a) 89 to 120

The reactions in Synthetic Example^(a) 88 were carried out insubstantially the same manners except that piperidin-4-carbonitrile,3-aminopropanenitrile, morpholine, 4-aminobenzonitrile,4-(aminomethyl)benzonitrile hydrochloride, (S)-3-fluoropyrrolidine,(R)-3-fluoropyrrolidine, 3,3-dimethylazetidine hydrochloride,4,4-difluoropiperidine hydrochloride,[4-(trifluoromethyl)phenyl]methanamine, 4-(trifluoromethyl)aniline,4-fluoroaniline, (4-fluorophenyl)methanamine, 4-fluoro-N-methylaniline,4-amino-3-methylbenzonitrile, 2-methyl-4-(trifluoromethoxy)aniline,4-amino-2-(trifluoromethyl)benzonitrile,(5-methylthiophen-2-yl)methanamine hydrochloride, 2-fluoroethanaminehydrochloride, 4-(methylamino)benzonitrile,1-(3,4-difluorophenyl)ethanamine,[4-(trifluoromethoxy)phenyl]methanamine, 2-(4-fluorophenyl)ethanamine,[4-fluoro-3-(trifluoromethyl)phenyl]methanamine,[4-(methylsulfonyl)phenyl]methanamine, 4-(trifluoromethoxy)aniline,2-chloro-4-(triluforomethoxy)aniline, 2-amino-5-fluorobenzonitrile,4-fluoro-2-(trifluoromethyl)aniline, 4-morpholinoaniline,(S)-pyrrolidin-3-ol hydrochloride or(S)-(tetrahydrofuran-2-yl)methanamine was used instead of thiomorpholine1,1-dioxide to give the compounds of Synthetic Examples^(a) 89 to 120.The names, morphologies and yields of the compounds synthesized areshown in Tables^(a) 10 to 12.

TABLE^(a) 10 Ex Compound Name Morphology Yield 891-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 83%5-c]pyrimidin-1-yl)cyclohexyl]methyl}piperidine- 4-carbonitrile 903-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 74%5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)propanenitrile 914-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 73%5-c]pyrimidin-1-yl)cyclohexyl]methyl}morpholine 924-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 57%5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)benzonitrile 934-[({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 64%5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)methyl]benzonitrile 941-(trans-4-{[(S)-3-fluoropyrrolidin-1- colorless solid 80%yl]methyl}cyclohexyl)-7H-pyrrolo[3,2-e][1, 2,3]triazolo[1,5-c]pyrimidine95 1-(trans-4-{[(R)-3-fluoropyrrolidin-1- colorless solid 63%yl]methyl}cyclohexyl)-7H-pyrrolo[3,2-e][1, 2,3]triazolo[1,5-c]pyrimidine96 1-{trans-4-[(3,3-dimethylazetidin-1-yl)methyl]cyclohexyl}- colorlesssolid 37% 7H-pyrrolo[3,2-e][1, 2,3]triazolo[1,5-c]pyrimidine 971-{trans-4-[(4,4-difluoropiperidin-1-yl)methyl]cyclohexyl}- colorlesssolid 64% 7H-pyrrolo[3,2-e][1, 2,3]triazolo[1,5-c]pyrimidine 981-[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 59%5-c]pyrimidin-1-yl)cyclohexyl]- N-[4-(trifluoromethyl)benzyl]methanamine99 N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 63%5-c]pyrimidin-1-yl)cyclohexyl]methyl}- 4-(trifluoromethyl)aniline 100N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 31%5-c]pyrimidin-1-yl)cyclohexyl]methyl}- 4-fluoroaniline 1011-[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 67%5-c]pyrimidin-1-yl)cyclohexyl]- N-(4-fluorobenzyl)methanamine 102N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 78%5-c]pyrimidin-1-yl)cyclohexyl]methyl}- 4-fluoro-N-methylaniline 1034-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 82%5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)- 3-methylbenzonitrile

TABLE^(a) 11 Ex Compound Name Morphology Yield 104N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 66%5-c]pyrimidin-1-yl)cyclohexyl]methyl}-2-methyl-4-(trifluoromethoxy)aniline 1054-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 61%5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)-2-(trifluoromethyl)benzonitrile 106 1 [trans 4 (7H pyrrolo[3,2e][1,2,3]triazolo[1, colorless solid 49% 5-c]pyrimidin-1-yl)cyclohexyl]-N-[(5-methylthiophen-2-yl)methyl]methanamine 107N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 19%5-c]pyrimidin-1-yl)cyclohexyl]methyl}- 2-fluoroethanamine 1084-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 36%5-c]pyrimidin-1-yl)cyclohexyl]methyl}(methyl)amino)benzonitrile 109N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 8.1% 5-c]pyrimidin-1-yl)cyclohexyl]methyl}- 1-(3,4-difluorophenyl)ethanamine110 1 [trans 4 (7H pyrrolo[3,2 e][1,2,3]triazolo[1, colorless solid 16%5-c]pyrimidin-1-yl)cyclohexyl]-N-[4-(trifluoromethoxy)benzyl]methanamine 111N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, pale purple 12%5-c]pyrimidin-1-yl)cyclohexyl]methyl}- solid2-(4-fluorophonyl)ethanamine 1121-[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 5.1% 5-c]pyrimidin-1-yl)cyclohexyl]-N-[4-fluoro-3-(trifluoromethyl)benzyl]methanamine 1131-[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 5.0% 5-c]pyrimidin-1-yl)cyclohexyl]- N-[4-(methylsulfonyl)benzyl]methanamine114 N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 69%5-c]pyrimidin-1-yl)cyclohexyl]methyl}- 4-(trifluoromethoxy)aniline 115N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 77%5-c]pyrimidin-1-yl)cyclohexyl]methyl}-2-chloro-4-(trifluoromethoxy)aniline 1162-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 59%5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)- 5-fluorobenzonitrile

TABLE^(a) 12 Ex Compound Name Morphology Yield 117N-{[trans-4-(7H-pyrrolo[3,2- colorless solid 63%e][1,2,3]triazolo[1,5-c]pyrimidin-1- yl)cyclohexyl]methyl}-4-fluoro-2-(trifluoromethyl)aniline 118 N-{[trans-4-(7H-pyrrolo[3,2- colorlesssolid 58% e][1,2,3]triazolo[1,5-c]pyrimidin- 1-yl)cyclohexyl]methyl}-4-morpholinoaniline 119 (S)-1-{[trans-4-(7H-pyrrolo[3,2-e][1,2, paleyellow 45% 3]triazolo[1,5-c]pyrimidin-1- solidyl)cyclohexyl]methyl}pyrrolidin-3-ol 120 1-[trans-4-(7H-pyrrolo[3,2-colorless solid 33% e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]-N-{[(S)-tetrahydrofuran-2- yl]methyl}methanamine

Synthetic Example^(a) 1214-{[4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]amino}benzonitrile

4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanone(21.5 mg, 0.0842 mmol) obtained in Synthetic Example^(a) 82 in a mixtureof methanol (1 mL) and acetic acid (0.1 mL) was stirred with4-aminobenzonitrile (15.0 mg, 0.126 mmol) and 2-picoline borane (13.5mg, 0.126 mmol) at room temperature for one day. The reaction mixturewas concentrated under reduced pressure, and the residue was purified bysilica gel thin layer chromatography (NH-PLC05 plate manufactured byFuji Silysia Chemical Ltd.: ethyl acetate) to give cis/trans mixture ofthe title compound as a pale yellow solid (17.1 mg, yield 57%).

Synthetic Examples^(a) 122 to 133

The reactions in Synthetic Example^(a) 121 were carried out insubstantially the same manners except that 2-(pyridin-4-yl)ethanamine,2-phenylethanamine, morpholine, 2-[3-(trifluoromethyl)phenyl]ethanamine,2-morpholinoethanamine, piperidine-4-carbonitrile,4-(trifluoromethyl)aniline, 4-amino-3-fluorobenzonitrile,4-fluoro-N-methylaniline, 4-fluoroaniline, 4-amino-3-methylbenzonitrileor 2-methyl-4-(trifluoromethoxy)aniline was used instead of4-aminobenzonitrile to give the compounds of Synthetic Examples^(a) 122to 133. The names, morphologies and yields of the compounds synthesizedare shown in Table^(a) 13.

TABLE^(a) 13 Ex Compound Name Morphology Yield 122N-[2-(pyridin-4-yl)ethyl]-4-(7H-pyrrolo[3, colorless solid 49%2-e][1,2,3]triazolo[1,5-c]pyrimidin- 1-yl)cyclohexanamine 123N-phenethyl-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 33%5-c]pyrimidin-1-yl)cyclohexanamine 1244-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, pale brown solid 28%5-c]pyrimidin-1-yl)cyclohexyl]morpholine 1254-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless oil 2.2% 5-c]pyrimidin-1-yl)-N-[3-(trifluoromethyl)phenethyl]cyclohexanamine 126N-(2-morpholinoethyl)-4-(7H-pyrrolo[3, gray amorphous 59%2-e][1,2,3]triazolo[1,5-c]pyrimidin-1- yl)cyclohexanamine 1271-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 67%5-c]pyrimidin-1-yl)cyclohexyl]piperidine- 4-carbonitrile 128N-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, pale yellow 71%5-c]pyrimidin-1-yl)cyclohexyl]-4-(trifluoromethyl)aniline solid 1294-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 8.8% 5-c]pyrimidin-1-yl)cyclohexyl]amino}- 3-fluorobenzonitrile 130N-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 63%5-c]pyrimidin-1-yl)cyclohexyl]-4-fluoro- N-methylaniline 131N-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 59%5-c]pyrimidin-1-yl)cyclohexyl]-4-fluoroaniline 1324-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 23%5-c]pyrimidin-1-yl)cyclohexyl]amino}- 3-methylbenzonitrile 133N-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 22%5-c]pyrimidin-1-yl)cyclohexyl]-2-methyl- 4-(trifluoromethoxy)aniline

Synthetic Example^(a) 134 134a:4-{[cis-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]amino}benzonitrile134b:4-{[(trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]amino}benzonitrile

4-{[4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]amino}benzonitrile(16.5 mg, 0.462 mmol) obtained in Synthetic Example^(a) 121 was resolvedby silica gel thin layer chromatography (hexane/ethyl acetate=1/2 (v/v))into4-{[cis-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]amino}benzonitrile(Synthetic Example^(a) 134a; pale yellow solid, 7.3 mg, yield 44%) in aless polar fraction and into4-{[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]amino}benzonitrile(Synthetic Example′ 134b, pale yellow solid, 3.0 mg, yield 18%) in amore polar fraction.

Synthetic Example^(a) 135 135a:cis-N-Phenethyl-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanamine135b:trans-N-Phenethyl-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[,1,5-c]pyrimidin-1-yl)cyclohexanamine

The reactions in Synthetic Example^(a) 134 were carried out insubstantially the same manners except thatN-phenethyl-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanamineobtained in Synthetic Example^(a) 123 was used instead of4-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]amino}benzonitrileto givecis-N-phenethyl-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanamine(Synthetic Example^(a) 135a, colorless solid, 3.22 mg, yield 16%) in aless polar fraction andtrans-N-phenethyl-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanamine(Synthetic Example^(a) 135b, colorless solid, 2.52 mg, yield 11%) in amore polar fraction.

Synthetic Example^(a) 136 136a:cis-N-(3-Phenylpropyl)-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanamine136b:trans-N-(3-Phenylpropyl)-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[,1,5-c]pyrimidin-1-yl)cyclohexanamine

4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanone(30.0 mg, 0.118 mmol) obtained in Synthetic Example^(a) 82 in a mixtureof methanol (1.5 ml) and acetic acid (0.15 mL) was mixed with3-phenylpropan-1-amine (25.0 μL, 0.176 mmol) at room temperature andstirred at 40° C. for 30 minutes. The reaction mixture was allowed tocool to room temperature and stirred with 2-picoline borane (19.0 mg,0.176 mmol) at room temperature for one day. After addition of 1 Mhydrochloric acid and ethyl acetate, the aqueous layer was separated,and after addition of 1 M aqueous sodium hydroxide, extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure, and the residue was purified bysilica gel chromatography (Hi Flash amino silica gel column manufacturedby Yamazen Corporation: ethyl acetate/hexane=1/1 (v/v)→ethyl acetate) togivecis-N-(3-phenylpropyl)-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanamine(Synthetic Example^(a) 136a; colorless oil, 6.00 mg, yield 13%) in aless polar fraction andtrans-N-(3-phenylpropyl)-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanamine(Synthetic Example^(a) 136b; colorless solid, 2.52 mg, yield 5.7%) in amore polar fraction.

Synthetic Examples^(a) 137 to 139

The reactions in Synthetic Example^(a) 136 were carried out insubstantially the same manners except that 4-(aminomethyl)benzonitrile,[4-(trifluoromethyl)phenyl]methanamine or morpholin-4-amine was usedinstead of 3-phenylpropan-1-amine to give the compounds of SyntheticExamples^(a) 137a to 139a in less polar fractions and the compounds ofSynthetic Examples^(a) 137b to 139b in more polar fractions. The names,morphologies and yields of the compounds synthesized are shown inTable^(a) 14.

TABLE^(a) 14 Ex Compound Name Morphology Yield 137a4-({[cis-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 39% 5c]pyrimidin 1 yl)cyclohexyl]amino}methyl)benzonitrile 137b4-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 40%5-c]pyrimidin-1-yl)cyclohexyl]amino}methyl)benzonitrile 138acis-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 51%5-c]pyrimidin-1-yl)-N-[4-(trifluoromethyl)benzyl]cyclohexanamine 138btrans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 30%5-c]pyrimidin-1-yl)-N-[4-(trifluoromethyl)benzyl]cyclohexanamine 139aN-[cis-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, Pale yellow 21%5-c]pyrimidin-1-yl)cyclohexyl]morpholin- solid 4-amine 139bN-[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, Pale yellow 17%5-c]pyrimidin-1-yl)cyclohexyl]morpholin- solid 4-amine

Synthetic Example^(a) 140[4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)phenyl]methanol

1-(4-{[(tert-Butyldimethylsilyl)oxy]methyl}phenyl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine(3.58 g, 9.43 mmol) obtained in Reference Synthetic Example^(a) 88 in amixture of dichloromethane (20 mL) and methanol (50 mL) was stirred withpyridinium p-toluenesulfonate (1.18 g, 4.72 mmol) at 60° C. for 8 hours.The reaction mixture was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (hexane/ethylacetate=1/1 (v/v)→ethyl acetate→ethyl acetate/methanol=1/1 (v/v)) togive the title compound as an ivory solid (831 mg, yield 33%).

Synthetic Example^(a) 141[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methanol

The reactions in Synthetic Example^(a) 140 were carried out insubstantially the same manners except that1-(trans-4-{[(tert-butyldimethylsilyl)oxy]methyl}cyclohexyl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidineobtained in Reference Synthetic Example^(a) 92 was used instead of1-(4-{[(tert-butyldimethylsilyl)oxy]methyl}phenyl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidineto give the title compound as a pale yellow solid (2.05 g, yield 78%).(alternative to Synthetic Example^(a) 10).

Synthetic Examples^(a) 142 to 144

The reactions in Synthetic Example^(a) 32 were carried out insubstantially the same manners except that1-(bromomethyl)-2-fluorobenzene,2-(bromomethyl)-5-(trifluoromethyl)furan or5-(bromomethyl)thiophene-2-carbonitrile (Reference Synthetic Example^(a)93) was used instead of benzyl bromide to give the compounds ofSynthetic Examples^(a) 142 to 144. The names, morphologies and yields ofthe compounds synthesized are shown in Table^(a) 15.

TABLE^(a) 15 Ex Compound Name Morphology Yield 1421-[1-(2-fluorobenzyl)piperidin-4-yl]-7H- colorless solid 11%pyrrolo[3,2-e][1,2,3]triazolo[1,5- c]pyrimidine 1431-(1-{[5-(trifluoromethyl)furan-2- colorless solid 4.0% yl]methyl}piperidin-4-yl)-7H- pyrrolo[3,2-e][1, 2,3]triazolo[1,5-c]pyrimidine 144 5-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorlesssolid 15% 5-c]pyrimidin-1-yl)piperidin-1-yl]methyl}thiophone-2-carbonitrile

Synthetic Examples^(a) 145 to 171

The reactions in Synthetic Example^(a) 44 were carried out insubstantially the same manners except that 6-fluoronicotinaldehyde,furan-2-carbaldehyde, 5-iodofuran-2-carbaldehyde,thiophene-2-carbaldehyde, 5-bromofuran-2-carbaldehyde,2-chlorothiazole-5-carbaldehyde, 1H-pyrazole-5-carbaldehyde,1,2,3-thiadiazole-4-carbaldehyde, 2-bromothiazole-5-carbaldehyde,4-fluoro-3-(trifluoromethyl)benzaldehyde,4-chloro-3-(trifluoromethyl)benzaldehyde,4-(methylsulfonyl)benzaldehyde,2-fluoro-4-(trifluoromethyl)benzaldehyde, 4-chloro-2-fluorobenzaldehyde,4-chloro-3-fluorobenzaldehyde, 2-chloroisonicotinaldehyde,3-fluoroisonicotinaldehyde, 5-fluoropyridine-2-carbaldehyde,3-chloroisonicotinaldehyde, 2,4-difluorobenzaldehyde,2-chloro-4-fluorobenzaldehyde, 3,4-difluorobenzaldehyde,3-fluoro-4-(trifluoromethyl)benzaldehyde,4-(2-hydroxyethoxy)benzaldehyde,4-(1,1,2,2-tetrafluoroethoxy)benzaldehyde, 6-methoxynicotinaldehyde ortert-butyl(2-oxoethyl)carbamate was used instead ofthiazole-5-carbaldehyde to give the compounds of Synthetic Examples^(a)145 to 171. The names, morphologies and yields of the compoundssynthesized are shown in Tables^(a) 16 and 17.

TABLE^(a) 16 Ex Compound Name Morphology Yield 1451-{1-[(6-fluoropyridin-3- colorless solid 66%yl)methyl]piperidin-4-yl}-7H-pyrrolo[3,2- e][1,2,3]triazolo[1,5-c]pyrimidine 146 1-[1-(furan-9-ylmethyl)piperidin-4-yl]- colorlesssolid 7.0%  7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5- c]pyrimidine 1471-{1-[(5-iodofuran-2-yl)methyl]piperidin- colorless solid 66%4-yl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine 1481-[1-(thiophen-2-ylmethyl)piperidin-4- colorless solid 49%yl]-7H-pyrrolo[3,2-e][1,2,3]-triazolo[1, 5-c]pyrimidine 1491-{1-[(5-bromofuran-2- colorless solid 56%yl)methyl]piperidin-4-yl}-7H-pyrrolo[3,2- e][1,2,3]triazolo[1,5-c]pyrimidine 150 5-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorlesssolid 62% 5-c]pyrimidin-1-yl)piperidin-1-yl]methyl}- 2-chlorothiazole151 1-{1-[(1H-pyrazol-5-yl)methyl]piperidin- colorless solid 17%4-yl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine 1524-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 45%5-c]pyrimidin-1-yl)piperidin-1-yl]methyl}- 1,2,3-thiadiazole 1535-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 58%5-c]pyrimidin-1-yl)piperidin-1-yl]methyl}- 2-bromothiazole 1541-{1-[4-fluoro-3- colorless solid 27%(trifluoromethyl)benzyl]piperidin-4-yl}- 7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5- c]pyrimidine 155 1-{1-[4-chloro-3- colorless solid9.0%  (trifluoromethyl)benzyl]piperidin-4-yl}- 7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5- c]pyrimidine 1561-{1-[4-(methylsulfonyl)benzyl]piperidin- colorless solid 21%4-yl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine 1571-{1-[2-fluoro-4- colorless solid 8.0% (trifluoromethyl)benzyl]piperidin-4-yl}- 7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5- c]pyrimidine 1581-[1-(4-chloro-2-fluorobenzyl)piperidin- colorless solid 50%4-yl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine 1591-[1-(4-chloro-3-fluorobenzyl)piperidin- colorless solid 44%4-yl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine 1601-{1-[(2-chloropyridin-4- colorless solid 39%yl)methyl]piperidin-4-yl}-7H-pyrrolo[3,2- e][1,2,3]triazolo[1,5-c]pyrimidine

TABLE^(a) 17 Ex Compound Name Morphology Yield 1611-{1-[(3-fluoropyridin-4- colorless solid 22%yl)methyl]piperidin-4-yl}-7H-pyrrolo[3,2- e][1,2,3]triazolo[1,5-c]pyrimidine 162 1-{1-[(5-fluoropyridin-2- colorless solid 39%yl)methyl]piperidin-4-yl}-7H-pyrrolo[3,2- e][1,2,3]triazolo[1,5-c]pyrimidine 163 1-{1-[(3-chloropyridin-4- colorless solid 33%yl)methyl]piperidin-4-yl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine 1641-[1-(2,4-difluorobenzyl)piperidin-4-yl]- pink solid 17%7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5- c]pyrimidine 1651-[1-(2-chloro-4-fluorobenzyl)piperidin- colorless solid 18%4-yl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5- c]pyrimidine 1661-[1-(3,4-difluorobenzyl)piperidin-4-yl]- colorless solid 30%7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine 167 1-{1-[3-fluoro-4-colorless solid 15% (trifluoromethyl)benzyl]piperidin-4-yl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5- c]pyrimidine 1682-(4-{[4-(7H-pyrrolo[3,2- colorless solid 7.0% e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidin-1-yl]methyl}phenoxy)ethanol 169 1-{1-[4-(1,1,2,2- colorlesssolid 11% tetrafluoroethoxy)benzyl]piperidin-4-yl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5- c]pyrimidine 1701-{1-[(6-methoxypyridin-3- colorless solid 15%yl)methyl]piperidin-4-yl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine 171 tert-butyl pale yellow 75%{2-[4-(7H-pyrrolo[3,2- amorphous e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidin-1-yl]ethyl}carbamate

Synthetic Examples^(a) 172 to 193

The reactions in Synthetic Example^(a) 88 were carried out insubstantially the same manners except that3-amino-1,1,1-trifluoro-2-phenylpropan-2-ol (Reference SyntheticExample^(a) 101), 4-[(trifluoromethyl)sulfonyl]aniline,2-phenylethanamine, 2-(trifluoromethyl)-1H-benzo[d]imidazol-6-amine,4-chloroaniline, (4-chlorophenyl)methanamine,2-(4-chlorophenyl)ethanamine, 5-fluoroindoline,3,3′-azanediyldipropanenitrile, (S)—N,N-dimethylpyrrolidin-3-amine,(5-methylfuran-2-yl)methanamine, (5-methylpyrazin-2-yl)methanamine,(S)-1-aminopropan-2-ol, (R)-1-aminopropan-2-ol, 2-amino-1-phenylethanol,(S)-pyrrolidine-3-carbonitrile hydrochloride, 2,2,2-trifluoroethanamine,5-(methylsulfonyl)indoline, N,N-dimethylindoline-5-sulfonamide,1-(2-aminoethyl)imidazolidin-2-on, 2-(1H-imidazol-4-yl)ethanaminedihydrochloride or phenylmethanamine was used instead of thiomorpholine1,1-dioxide to give the compounds of Synthetic Examples^(a) 172 to 193.The names, morphologies and yields of the compounds synthesized areshown in Tables^(a) 18 and 19.

TABLE^(a) 18 Ex Compound Name Morphology Yield 1723-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 31%5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)-1,1,1-trifluoro-2-phenylpropan- 2-ol 173N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 10%5-c]pyrimidin-1-yl)cyclohexyl]methyl}-4-[(trifluoromethyl)sulfonyl]aniline 174N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 97%5-c]pyrimidin-1-yl)cyclohexyl]methyl}- 2-phenylethanamine 175N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 15%5-c]pyrimidin-1-yl)cyclohexyl]methyl}-2-(trifluoromethyl)-1H-benzo[d]imidazol- 5-amine 176N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 52%5-c]pyrimidin-1-yl)cyclohexyl]methyl}- 4-chloroaniline 1771-[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 37%5-c]pyrimidin-1-yl)cyclohexyl]- N-(4-chlorobenzyl)methanamine 178N-{[trans-4-(7H-pyrrolo[3,2c][1,2,3]triazolo[1, pale purple 86% 5c]pyrimidin 1 yl)cyclohexyl]methyl}- solid 2-(4-chlorophenyl)ethanamine179 1-[trans-4-((5-fluoroindolin-1-yl)methyl)cyclohexyl]- colorlesssolid 83% 7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine 1803,3′-({[trans-4-(7H-pyrrolo[3,2-c][1,2,3]triazolo[1, colorless solid 74%5-c]pyrimidin-1-yl)cyclohexyl]methyl}azanediyl)dipropanenitrile 181(S)-1-{[trans-4-(7H-pyrrolo[3,2-e][1,2, colorless solid 71%3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}-N,N-dimethylpyrrolidin-3-amine 1821-[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, pale yellow 44%5-c]pyrimidin-1-yl)cyclohexyl]- solidN-[(5-methylfuran-2-yl)methyl]methanamine 1831-[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 55%5-c]pyrimidin-1-yl)cyclohexyl]-N-[(5-methylpyrazin-2-yl)methyl]methanamine 184(S)-1-({[trans-4-(7H-pyrrolo[3,2-e][1, colorless solid 21%2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)propan- 2-ol185 (R)-1-({[trans-4-(7H-pyrrolo[3,2-e][1, colorless solid 20%2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)propan- 2-ol

TABLE^(a) 19 Ex Compound Name Morphology Yield 1862-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 24%5-c]pyrimidin-1-yl)cyclohexyl]methyl]amino)- 1-phenylethanol 187(S)-1-{[trans-4-(7H-pyrrolo[3,2-e][1,2, colorless solid 71%triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}pyrrolidine-3-carbonitrile 188 N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,colorless solid 48% 5-c]pyrimidin-1-yl)cyclohexyl]methyl}-2,2,2-trifluoroethanamine 189 1-(trans-4-{[5-(methylsulfonyl)indolin-colorless solid 57% 1-yl]methyl}cyclohexyl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine 1901-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 72%5-c]pyrimidin-1-yl)cyclohexyl]methyl}-N,N-dimethylindoline-5-sulfonamide 1911-[2-({[trans-4-(7H-pyrrolo[3,2-e][1,2, colorless solid 33%3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)ethyl]imidazolidin- 2-one 192N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 56%5-c]pyrimidin-1-yl)cyclohexyl]methyl}- 2-(1H-imidazol-4-yl)ethanaminehydrochloride 193 1-[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,colorless solid 84% 5-c]pyrimidin-1-yl)cyclohexyl]- N-benzylmethanamine

Synthetic Examples^(a) 194 to 197

The reactions in Synthetic Example^(a) 136 were carried out insubstantially the same manners except that phenylmethanamine,(4-fluorophenyl)methanamine, 3-amino-1,1,1-trifluoro-2-phenylpropan-2-ol(Reference Synthetic Example^(a) 101) or (4-chlorophenyl)methanamine wasused instead of 3-phenylpropan-1-amine to give the compounds ofSynthetic Examples^(a) 194a to 197a in less polar fractions and thecompounds of Synthetic Examples^(a) 194b to 197b in more polarfractions. The names, morphologies and yields of the compoundssynthesized are shown in Table^(a) 20.

TABLE^(a) 20 Ex Compound Name Morphology Yield 194acis-N-benzyl-4-(7H-pyrrolo[3,2-e][1,2, colorless solid 44%3]triazolo[1,5-c]pyrimidin-1- yl)cyclohexanamine 194btrans-N-benzyl-4-(7H-pyrrolo[3,2-e][1, colorless solid 37%2,3]triazolo[1,5-c]pyrimidin-1- yl)cyclohexanamine 195acis-N-(4-fluorobenzyl)-4-(7H-pyrrolo[3, colorless solid 30%2-e][1,2,3]triazolo[1,5-c]pyrimidin- 1-yl)cyclohexanamine 195btrans-N-(4-fluorobenzyl)-4-(7H-pyrrolo[3, colorless solid 24%2-e][1,2,3]triazolo[1,5-c]pyrimidin- 1-yl)cyclohexanamine 196a3-{[cis-4-(7H-pyrrolo[3,2-e- colorless solid 34%][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]amino}-1,1,1-trifluoro- 2-phenylpropan 2 ol 196b3-{[trans-4-(7H-pyrrolo[3,2- colorless solid 39%e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]amino}-1,1,1-trifluoro-2- phenylpropan-2-ol 197acis-N-(4-chlorobenzyl)-4-(7H-pyrrolo[3, colorless solid 15%2-e][1,2,3]triazolo[1,5-c]pyrimidin- 1-yl)cyclohexanamine 197btrans-N-(4-chlorobenzyl)-4-(7H-pyrrolo[3, colorless solid 24%2-e][1,2,3]triazolo[1,5-c]pyrimidin- 1-yl)cyclohexanamine

Synthetic Examples^(a) 198 to 204

The reactions in Synthetic Example^(a) 136 were carried out insubstantially the same manners except that 2-(4-chlorophenyl)ethanamine,3-amino-2-(4-chlorophenyl)-1,1,1-trifluoropropan-2-ol (ReferenceSynthetic Example^(a) 100),3-amino-1,1,1-trifluoro-2-(4-fluorophenyl)propan-2-ol (ReferenceSynthetic Example^(a) 102), 2-(4-fluorophenyl)ethanamine,2-amino-1-phenylethanol, (S)-2-amino-1-phenylethanol or(R)-2-amino-1-phenylethanol was used instead of 3-phenylpropan-1-amineto give the compounds of Synthetic Examples^(a) 198 b to 204b in morepolar fractions. The names, morphologies and yields of the compoundssynthesized are shown in Table^(a) 21.

TABLE^(a) 21 Ex Compound Name Morphology Yield 198btrans-N-(4-chlorophenethyl)-4-(7H-pyrrolo[3, colorless solid 17%2-e][1,2,3]triazolo[1,5-c]pyrimidin- 1-yl)cyclohexanamine 199b3-((trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, pale green solid 37%5-c]pyrimidin-1-yl)cyclohexyl)amino)-2-(4-chlorophenyl)-1,1,1-trifluoropropan- 2-ol 200b3-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, pale green solid 42%5-c]pyrimidin-1-yl)cyclohexyl]amino}-1,1,1-trifluoro-2-(4-fluorophenyl)propan- 2-ol 201btrans-N-(4-fluorophenethyl)-4-(7H-pyrrolo[3, colorless solid 24%2-e][1,2,3]triazolo[1,5-c]pyrimidin- 1-yl)cyclolhexnamine 202b2-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 8.0% 5-c]pyrimidin-1-yl)cyclohexyl]amino}- 1-phenylethanol 203b(S)-2-{[trans-4-(7H-pyrrolo[3,2-e][1, pale yellow 26%2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]amino}-1- solidphenylethanol 204b (R)-2-{[trans-4-(7H-pyrrolo[3,2-e][1, colorless solid9.0%  2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]amino}-1-phenylethanol

Synthetic Example^(a) 205N-[4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]-4-chloroaniline

The reactions in Synthetic Example^(a) 121 were carried out insubstantially the same manners except that 4-chloroaniline was usedinstead of 4-aminobenzonitrile to give the title compound as a colorlesssolid (10.2 mg, yield 28%).

Synthetic Example^(a) 206trans-N-(4-Fluorophenyl)-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[,1,5-c]pyrimidin-1-yl)cyclohexanecarboxamide

trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanecarboxylicacid (19.5 mg, 0.0683 mmol) obtained in Synthetic Example^(a) 80 inN,N-dimethylformamide (1.5 mL) was mixed with 4-fluoroaniline (0.0977mL, 0.102 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (38.8 mg, 0.102 mmol) and then withN,N-diisopropylethylamine (0.0238 mL, 0.137 mmol) and stirred at roomtemperature for 3 hours. After addition of water, the reaction mixturewas extracted with ethyl acetate, and the organic layer was washed withsaturated aqueous sodium chloride, dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel thin layer chromatography (NH-PLC05 plate manufactured byFuji Silysia Chemical Ltd.: ethyl acetate). The resulting solid waswashed with methanol to give the title compound as a colorless solid(6.45 mg, yield 25%).

Synthetic Examples^(a) 207 to 209

The reactions in Synthetic Example^(a) 206 were carried out insubstantially the same manners except that (4-fluorophenyl)methanamine,2-(4-fluorophenyl)ethanamine or (S)-3-fluoropyrrolidine was used insteadof 4-fluoroaniline to give the compounds of Synthetic Examples^(a) 207to 209. The names, morphologies and yields of the compounds synthesizedare shown in Table^(a) 22.

TABLE^(a) 22 Ex Compound Name Morphology Yield 207trans-N-(4-fluorobenzyl)-4-(7H-pyrrolo[3, colorless solid 56%2-c][1,2,3]triazolo[1,5-c]pyrimidin- 1-yl)cyclohexanecarboxamide 208trans-N-(4-fluorophenethyl)-4-(7H-, colorless solid 48%pyrrolo[32-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanecarboxamide 209 [trans-4-(7H-pyrrolo[3,2-colorless solid 31% e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl][(S)-3-fluoropyrrolidin-1- yl]methanone

Synthetic Example^(a) 2104-{[4-(7H-Imidazo[1,5-c]pyrrolo[3,2-e]pyrimidin-1-yl)piperidin-1-yl]methyl}benzonitrile

The reactions in Synthetic Example^(a) 3 were carried out insubstantially the same manners except that4-{[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-imidazo[1,5-c]pyrrolo[3,2-e]pyrimidin-1-yl)piperidin-1-yl]methyl}benzonitrileobtained in Reference Synthetic Example^(a) 97 was used instead ofbenzyl3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-imidazo[1,5-c]pyrrolo[3,2-e]pyrimidin-1-yl)piperidine-1-carboxylateto give the title compound as a brown solid (1.3 mg, yield 4%).

Synthetic Example^(a) 211 Benzyl3-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)pyrrolidine-1-carboxylate

The reactions in Synthetic Example^(a) 5 were carried out insubstantially the same manners except that benzyl3-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)pyrrolidine-1-carboxylateobtained in Reference Synthetic Example^(a) 99 was used instead of(7H-pyrrolo[2,3-d]pyrimidin-4-yl)(o-tolyl)methanone to give the titlecompound as a colorless solid (27.4 mg, yield 2%).

Synthetic Example^(a) 2122-[4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidin-1-yl]-1-[4-(trifluoromethyl)phenyl]ethanol

1-(Piperidin-4-yl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidineacetate (33.1 mg, 0.110 mmol) obtained in Reference SyntheticExample^(a) 104 in ethanol (3 mL) was stirred with water (0.5 mL),triethylamine (0.1 mL), ytterbium (III) trifluoromethanesulfonate (12.7mg, 0.0237 mmol) and 2-[4-(trifluoromethyl)phenyl]oxirane (47.0 mg,0.250 mmol) obtained in Reference Synthetic Example^(a) 103 at 80° C.for 3 hours. After addition of water, the reaction mixture was extractedwith ethyl acetate, and the organic layer was washed with saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (methanol/chloroform, =1/20 (v/v)). Theresulting solid was washed with hexane/ethyl acetate to give the titlecompound as a red solid (19.7 mg, yield 42%).

Synthetic Examples^(a) 213 to 226

The reactions in Synthetic Example^(a) 44 were carried out insubstantially the same manners except that2-(4-formylphenoxy)acetonitrile (Reference Synthetic Example′ 105),6-chloronicotinaldehyde, (E)-3-(furan-2-yl)acrylaldehyde,1-methyl-1H-pyrrole-2-carbaldehyde, 3-chloro-1H-indazole-5-carbaldehyde,quinoxaline-6-carbaldehyde, oxazole-4-carbaldehyde,4-(difluoromethoxy)benzaldehyde, 4-(1H-imidazole-1-yl)benzaldehyde,2-fluoro-4-formylbenzonitrile, 2-fluoro-5-formylbenzonitrile,2,6-difluoro-4-(trifluoromethyl)benzaldehyde,3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde or4-[(2-cyanoethyl)methylamino]benzaldehyde was used instead ofthiazole-5-carbaldehyde to give the compounds of Synthetic Examples^(a)213 to 226. The names, morphologies and yields of the synthesizedcompounds are shown in Table^(a) 23.

TABLE^(a) 23 Ex Compound Name Morphology Yield 2132-(4-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 15%5-c]pyrimidin-1-yl)piperidin- 1-yl]methyl}phenoxy)acetonitrile 2141-{1-[(6-chloropyridin-3-yl)methyl]piperidin- colorless solid  8%4-yl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine 215(E)-1-{1-[3-(furan-2-yl)allyl]piperidin- colorless solid 33%4-yl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine 2161-(1-methylpiperidin-4-yl)-7H-pyrrolo[3, yellow solid 27%2-e][1,2,3]triazolo[1,5-c]pyrimidine 2171-{1-[(3-chloro-1H-indazol-5-yl)methyl]piperidin- colorless solid 4.0% 4-yl}-7H-pyrrolo[3,2-e][1, 2,3]triazolo[1,5-c]pyrimidine 2181-[1-(quinoxalin-6-ylmethyl)piperidin- colorless solid 42%4-yl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine 2194-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 23%5-c]pyrimidin-1-yl)piperidin-1-yl]methyl}oxazole 2201-{1-[4-(difluoromethoxy)benzyl]piperidin- colorless solid 21%4-yl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine 2211-{1-[4-(1H-imidazol-1-yl)benzyl]piperidin- yellow solid 64%4-yl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine 2224-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 44%5-c]pyrimidin-1-yl)piperidin-1-yl]methyl}- 2-fluorobenzonitrile 2235-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 61%5-c]pyrimidin-1-yl)piperidin-1-yl]methyl}- 2-fluorobenzonitrile 2241-{1-[2,6-difluoro-4-(trifluoromethyl)benzyl]piperidin- colorless solid26% 4-yl}-7H-pyrrolo[3, 2-e][1,2,3]triazolo[1,5-c]pyrimidine 2256-{[4-(7H-pyrrolo[3,2-c][1,2,3]triazolo[1, colorless solid 12%5-c]pyrimidin-1-yl)piperidin-1-yl]methyl}- 2H-benzo[b][1,4]oxazin-3(4H)-one 226 3-[(4-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid5.0%  5-c]pyrimidin-1-yl)piperidin-1-yl]methyl}phenyl)(methyl)amino]propanenitrile

Synthetic Example^(a) 2271-{1-[(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methyl]piperidin-4-yl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

1-(Piperidin-4-yl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidineacetate (20.0 mg, 0.0660 mmol) obtained in Reference SyntheticExample^(a) 104 in methanol (1 mL) was mixed with2,2-difluorobenzo[d][1,3]dioxole-5-carbaldehyde (20.0 μL, 0.0990 mmol),nicotinic acid (12.3 mg, 0.0990 mmol), and 2-picoline borane (10.7 mg,0.0990 mmol) and stirred at room temperature for 1 day. After additionof 1M aqueous sodium hydroxide, the reaction mixture was extracted withchloroform. The organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel thin layer chromatography (methanol/chloroform=1/10 (v/v)) togive the title compound as a colorless solid (13.1 mg, yield 48%).

Synthetic Examples^(a) 228 to 239

The reactions in Synthetic Example^(a) 227 were carried out insubstantially the same manners except that 5-chlorofuran-2-carbaldehyde,2,2-difluorobenzo[d][1,3]dioxol-4-carbaldehyde,3-oxo-2-phenylpropanenitrile, 2,6-dichloronicotinaldehyde,benzo[d]thiazole-2-carbaldehyde, 4,5-dibromothiophene-2-carbaldehyde,2-morpholinothiazole-5-carbaldehyde,2-(4-chlorophenyl)-3-oxopropanenitrile,5-methylthiophene-2-carbaldehyde, 4-bromothiophene-2-carbaldehyde,5-bromothiophene-2-carbaldehyde or isonicotinaldehyde was used insteadof 2,2-difluorobenzo[d][1,3]dioxole-5-carbaldehyde to give the compoundsof Synthetic Examples^(a) 228 to 239. The names, morphologies and yieldsof the synthesized compounds are shown in Table^(a) 24.

TABLE^(a) 24 Ex Compound Name Morphology Yield 2281-{1-[(5-chlorofuran-2-yl)methyl]piperidin- colorless solid 41%4-yl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine 2291-{1-[(2,2-difluorobenzo[d][1,3]dioxol- colorless solid 26%4-yl)methyl]piperidin-4-yl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine 230(Z)-3-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 22%5-c]pyrimidin-1-yl)piperidin- 1-yl]-2-phenylacrylonitrile 2311-{1-[(2,6-dichloropyridin-3-yl)methyl]piperidin- colorless solid 29%4-yl}-7H-pyrrolo[3,2-e][1, 2,3]triazolo[1,5-c]pyrimidine 2322-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 13%5-c]pyrimidin-1-yl)piperidin-1-yl]methyl}benzo[d]thiazole 2331-{1-[(4,5-dibromothiophen-2-yl)methyl]piperidin- colorless solid 40%4-yl}-7H-pyrrolo[3,2-e][1, 2,3]triazolo[1,5-c]pyrimidine 2344-(5-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 13%5-c]pyrimidin-1-yl)piperidin- 1-yl]methyl}thiazol-2-yl)morpholine 235(Z)-3-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, pale purple 5.0% 5-c]pyrimidin-1-yl)piperidin- solid1-yl]-2-(4-chlorophenyl)acrylonitrile 2361-{1-[(5-methylthiophen-2-yl)methyl]piperidin- pale orange 27%4-yl}-7H-pyrrolo[3,2-e][1,2, solid 3]triazolo[1,5-c]pyrimidine 2371-{1-[(4-bromothiophen-2-yl)methyl]piperidin- colorless solid 8.0% 4-yl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine 2381-{1-[(5-bromothiophen-2-yl)methyl]piperidin- colorless solid 41%4-yl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine 2391-[1-(pyridin-4-ylmethyl)piperidin-4- colorless solid 39%yl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine

Synthetic Examples^(a) 240 to 246

The reactions in Synthetic Example^(a) 32 were carried out insubstantially the same manners except that 4-(chloromethyl)thiazolehydrochloride, 4-(bromomethyl)benzamide (Reference Synthetic Example^(a)106), 4-(bromomethyl)phthalonitrile (Reference Synthetic Example^(a)108), 5-(bromomethyl)-2-(trifluoromethyl)benzonitrile (ReferenceSynthetic Example^(a) 107),4-(bromomethyl)-2-(trifluoromethyl)benzonitrile (Reference SyntheticExample^(a) 109), (1-bromoethyl)benzene or 2-chloroacetonitrile was usedinstead of benzylbromide to give the compounds of Synthetic Examples^(a)240 to 246. The names, morphologies and yields of the synthesizedcompounds are shown in Table^(a) 25.

TABLE^(a) 25 Ex Compound Name Morphology Yield 2404-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 21%5-c]pyrimidin-1-yl)piperidin-1-yl]methyl}thiazole 2414-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 24%5-c]pyrimidin-1-yl)piperidin-1-yl]methyl}benzamide 2424-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 71%5-c]pyrimidin-1-yl)piperidin-1-yl]methyl}phthalonitrile 2435-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 77%5-c]pyrimidin-1-yl)piperidin-1-yl]methyl}-2-(trifluoromethyl)benzonitrile 2444-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 68%5-c]pyrimidin-1-yl)piperidin-1-yl]methyl}-2-(trifluoromethyl)benzonitrile 2451-[1-(1-phenylethyl)piperidin-4-yl]-7H- pale purple 6.0% pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine solid 2462-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, pale purple 35%5-c]pyrimidin-1-yl)piperidin-1-yl]acetonitrile solid

Synthetic Examples^(a) 247 to 345

The reactions in Synthetic Example^(a) 88 were carried out insubstantially the same manners except that 4-amino-2-chlorobenzonitrile,4-amino-1-naphthonitrile, 3,4-difluoroaniline, 3,4,5-trifluoroaniline,4-fluoro-3-(trifluoromethyl)aniline, 5-amino-2-fluorobenzonitrile,3-aminodihydrothiophen-2(3H)-one hydrochloride, thiazolidine,2,2-difluoroethaneamine, 3,3,3-trifluoropropane-1-amine,3-hydroxyazetidine hydrochloride, 4-(trifluoromethyl)piperidinehydrochloride, 2-aminoacetonitrile hydrochloride, piperazin-2-one,piperidine-4-carboxamide, 4-aminophthalonitrile,5-amino-2-chlorobenzonitrile, 2-(4-aminophenyl)acetonitrile,(R)-pyrrolidine-2-yl methanol, (S)-pyrrolidine-2-yl methanol,(R)-pyrrolidin-3-ol, 2-(benzylamino)ethanol,2-bromo-2,2-difluoroethaneamine hydrochloride (Reference SyntheticExample^(a) 131), (4-methoxyphenyl)methanamine, piperidin-4-ol,2-aminoethanol, 7-amino-2H-benzo[b][1,4]oxazine-3(4H)-one,6-amino-2H-benzo[b][1,4]oxazine-3(4H)-one,2,2-difluorobenzo[d][1,3]dioxol-5-amine, (R)-2-amino-1-phenylethanol,(S)-2-amino-1-phenylethanol, azetidine-3-carboxylic acid,3-aminodihydrofuran-2(3H)-one hydrobromide, cyclopropylamine,azetidine-3-carbonitrile hydrochloride, 4-(2-aminoethyl)benzonitrile(Reference Synthetic Example^(a) 111), cyclobutanamine,cyclopentanamine, cyclopropylmethanamine, azetidine hydrochloride,pyrrolidine, (R)-4-aminoisoxazolidin-3-one,(R)-(tetrahydrofuran-2-yl)methanamine, 2,2-dimethylcyclopropanaminehydrochloride, 2-methylcyclopropanamine,1-(trifluoromethyl)cyclopropanamine, 1-(methoxymethyl)cyclopropanaminehydrochloride, oxetan-3-amine, 1-methylcyclopropanamine hydrochloride,dimethylamine hydrochloride, 2-(methylamino)ethanol, 2,2′-azanediyldiethanol, (R)-tert-butyl pyrrolidin-3-ylcarbamate,3-(phenylamino)propanenitrile, (R)-pyrrolidine-3-carbonitrilehydrochloride, 3-(methylamino)propanenitrile,(1s,3R,4r,5S,7s)-4-aminoadamantan-1-ol (Reference Synthetic Example^(a)129), (1s,3R,4s,5S,7s)-4-aminoadamantan-1-ol (Reference SyntheticExample^(a) 130), trans-4-aminocyclohexanol, 2-(cyclohexylamino)ethanol,tert-butyl(S)-pyrrolidin-3-ylcarbamate, 3-(4-chlorophenyl)oxetan-3-aminehydrochloride, 4-[4-chloro-3-(trifluoromethyl)phenyl]piperidin-4-ol,4-phenylpiperidine-4-carbonitrile hydrochloride,2-(piperidin-4-yl)propan-2-ol, cis-2-(aminomethyl)cyclohexanolhydrochloride, 1-(aminomethyl)cyclohexanol hydrochloride,3-(piperazin-1-yl)propanenitrile, 2-(piperazin-1-yl)ethanol,bicyclo[1.1.1]pentan-1-amine hydrochloride,1,1,1,3,3,3-hexafluoropropan-2-amine, (R)—N-(pyrrolidin-3-yl)acetamide,(S)—N-(pyrrolidin-3-yl)acetamide,(R)-2,2,2-trifluoro-N-(pyrrolidin-3-yl)acetamide hydrochloride,(S)-2,2,2-trifluoro-N-(pyrrolidin-3-yl)acetamide hydrochloride,3-(4-fluorophenyl)oxetan-3-amine hydrochloride,1-(4-fluorophenyl)cyclopropanamine hydrochloride,1-(4-fluorophenyl)cyclobutanamine hydrochloride,2-methoxy-N-methylethanamine, bis(2-methoxyethyl)amine,(1-aminocyclopropyl)methanol hydrochloride, 3,3-difluoropyrrolidinehydrochloride, methanamine hydrochloride, ethanamine hydrochloride,propan-2-amine, 2-methylpropan-2-amine, prop-2-yn-1-amine,4-(piperidin-4-yl)morpholine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate,tert-butyl(piperidin-4-ylmethyl)carbamate,tert-butyl(S)-3-aminopyrrolidine-1-carboxylate, 3-fluoroazetidinehydrochloride, 3,3-difluoroazetidine hydrochloride,(R)—N,N-dimethylpyrrolidin-3-amine,2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride,2,2,3,3,3-pentafluoropropan-1-amine, 3-amino-1,1,1-trifluoropropan-2-ol,thietan-3-amine hydrobromide or 1-(ethylsulfonyl)piperazine was usedinstead of thiomorpholine 1,1-dioxide to give the compounds of SyntheticExamples^(a) 247 to 345. The names, morphologies and yields of thesynthesized compounds are shown in Tables^(a) 26 to 33.

TABLE^(a) 26 Ex Compound Name Morphology Yield 2474-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 79%5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)- 2-chlorobenzonitrile 2484-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, pale pink solid 56%5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)- 1-naphthonitrile 249N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 47%5-c]pyrimidin-1-yl)cyclohexyl]methyl}- 3,4-difluoroaniline 250N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 65%5-c]pyrimidin-1-yl)cyclohexyl]methyl}- 3,4,5-trifluoroaniline 251N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 47%5-c]pyrimidin-1-yl)cyclohexyl]methyl}-4-fluoro-3-(trifluoromethyl)aniline 2525-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 69%5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)- 2-fluorobenzonitrile 2533-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 73%5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)dihydrothiophen- 2(3H)- one254 3-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, pale pink solid 21%5-c]pyrimidin-1-yl)cyclohexyl]methyl}thiazolidine 255N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, pale purple 62%5-c]pyrimidin-1-yl)cyclohexyl]methyl}- solid 2,2-difluoroethanamine 256N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 66%5-c]pyrimidin-1-yl)cyclohexyl]methyl}- 3,3,3-trifluoropropan-1-amine 2571-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 37%5-c]pyrimidin-1-yl)cyclohexyl]methyl}azetidin- 3-ol 2581-(trans-4-{[4-(trifluoromethyl)piperidin- colorless solid 94%1-yl]methyl}cyclohexyl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine 2592-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 27%5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)acetonitrile 2604-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 52%5-c]pyrimidin-1-yl)cyclohexyl]methyl}piperazin- 2-one

TABLE^(a) 27 Ex Compound Name Morphology Yield 2611-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 8.0% 5-c]pyrimidin-1-yl)cyclohexyl]methyl}piperidine- 4-carboxamide 2624-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 54%5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)phthalonitrile 2635-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 75%5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)- 2-chlorobenzonitrile 2642-[4-({[trans-4-(7H-pyrrolo[3,2-c][1, colorless solid 54%2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)phenyl]acetonitrile265 ((R)-1-{[trans-4-(7H-pyrrolo[3,2-e][1, colorless solid 71%2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}pyrrolidin-2-yl)methanol 266 ((S)-1-{[trans-4-(7H-pyrrolo[3,2-e][1, colorless solid87% 2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}pyrrolidin-2-yl)methanol 267 (R)-1-{[trans-4-(7H-pyrrolo[3,2-c][1, colorless solid68% 2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}pyrrolidin- 3-ol268 2-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid62% 5-c]pyrimidin-1-yl)cyclohexyl]methyl}(benzyl)amino)ethanol 269N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 42%5-c]pyrimidin-1-yl)cyclohexyl]methyl}- 2-bromo-2,2-difluoroethanamine270 1-[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 30%5-c]pyrimidin-1-yl)cyclohexyl]- N-(4-methoxybenzyl)methanamine 2711-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 54%5-c]pyrimidin-1-yl)cyclohexyl]methyl}piperidin- 4-ol 2722-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 34%5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)ethanol 2737-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 80%5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)- 2H-benzo[b][1,4]oxazin-3(4H)-one

TABLE^(a) 28 Ex Compound Name Morphology Yield 2746-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, pale pink solid 98%5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)- 2H-benzo[b][1,4]oxazin-3(4H)-one 275 N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorlesssolid 63% 5-c]pyrimidin-1-yl)cyclohexyl]methyl}-2,2-difluorobenzo[d][1,3]dioxol- 5-amine 276(R)-2-({[trans-4-(7H-pyrrolo[3,2-e][1, colorless solid 50%2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)-1-phenylethanol 277 (S)-2-({[trans-4-(7H-pyrrolo[3,2-e][1, colorlesssolid 73% 2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)-1-phenylethanol 278 1-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,colorless solid 90% 5-c]pyrimidin-1-yl)cyclohexyl]methyl}azetidine-3-carboxylic acid 279 3-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,colorless solid quant.5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)dihydrofuran- 2(3H)-one 280N-{[trans-4-(7H-pyrrolo[3,2-c][1,2,3]triazolo[1, colorless solid 34%5-c]pyrimidin-1-yl)cyclohexyl]methyl}cyclopropanamine 2811-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 46%5-c]pyrimidin-1-yl)cyclohexyl]methyl}azetidine- 3-carbonitrile 2824-[2-({[trans-4-(7H-pyrrolo[3,2-e][1, colorless solid 54%2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)ethyl]benzonitrile283 N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 70%5-c]pyrimidin-1-yl)cyclohexyl]methyl}cyclobutanamine 284N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 63%5-c]pyrimidin-1-yl)cyclohexyl]methyl}cyclopentanamine 2851-[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 53%5-c]pyrimidin-1-yl)cyclohexyl]- N-(cyclopropylmethyl)methanamine 2861-[trans-4-(azetidin-1-ylmethyl)cyclohexyl]- colorless solid 60%7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine

TABLE^(a) 29 Ex Compound Name Morphology Yield 2871-[trans-4-(pyrrolidin-1-ylmethyl)cyclohexyl]- colorless solid 64%7H-pyrrolo[3,2-e][1,2,3]triazolo[1, 5-c]pyrimidine 288(R)-4-({[trans-4-(7H-pyrrolo[3,2-e][1, colorless solid 78%2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)isoxazolidin-3-one 289 1-[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorlesssolid 46% 5-c]pyrimidin-1-yl)cyclohexyl]-N-{[(R)-tetrahydrofuran-2-yl]methyl}methanamine 290N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 44%5-c]pyrimidin-1-yl)cyclohexyl]methy}- 2,2-dimethylcyclopropanamine 291N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 53%5-c]pyrimidin-1-yl)cyclohexyl]methyl}- 2-methylcyclopropanamine 292N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 60%5-c]pyrimidin-1-yl)cyclohexyl]methyl}-1-(trifluoromethyl)cyclopropanamine 293N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 52%5-c]pyrimidin-1-yl)cyclohexyl]methyl}- 1-(methoxymethyl)cyclopropanamine294 N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 40%5-c]pyrimidin-1-yl)cyclohexyl]methyl}oxetan- 3-amine 295N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 25%5-c]pyrimidin-1-yl)cyclohexyl]methyl}- 1-methylcyclopropanamine 2961-[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 43%5-c]pyrimidin-1-yl)cyclohexyl]- N,N-dimethylmethanamine 2972-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 57%5-c]pyrimidin-1-yl)cyclohexyl]methyl}(methyl)amino)ethanol 2982,2′-({[trans-4-(7H-pyrrolo[3,2-e][1, colorless solid 43%2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}azanediyl)diethanol299 tert-butyl colorless solid 64%((R)-1-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}pyrrolidin-3-yl)carbamate

TABLE^(a) 30 Ex Compound Name Morphology Yield 3003-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 72%5-c]pyrimidin-1-yl)cyclohexyl]methyl}(phenyl)amino)propanenitrile 301(R)-1-{[trans-4-(7H-pyrrolo[3,2-e][1, colorless solid 58%2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}pyrrolidine-3-carbonitrile 302 3-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,colorless solid 42%5-c]pyrimidin-1-yl)cyclohexyl]methyl}(methyl)amino)propanenitrile 303(1S,3R,4r,5S,7S)-4-({[trans-4-(7H-pyrrolo[3, colorless solid 61%2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)adamantan- 1-ol 304(1S,3R,4s,5S,7S)-4-({[trans-4-(7H-pyrrolo[3, colorless solid 53%2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)adamantan- 1-ol 305trans-4-({[trans-4-(7H-pyrrolo[3,2-e][1, colorless solid 35%2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)cyclohexanol306 2-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid40% 5-c]pyrimidin-1-yl)cyclohexyl]methyl}(cyclohexyl)amino)ethanol 307tert-butyl colorless solid 69% ((S)-1-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}pyrrolidin-3-yl)carbamate 308 N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,colorless solid 72% 5-c]pyrimidin-1-yl)cyclohexyl]methyl}-3-(4-chlorophenyl)oxetan- 3-amine 3091-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 54%5-c]pyrimidin-1-yl)cyclohexyl]methyl}-4-[4-chloro-3-(trifluoromethyl)phenyl]piperidin- 4-ol 3101-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 56%5-c]pyrimidin-1-yl)cyclohexyl]methyl}- 4-phenylpiperidine-4-carbonitrile311 2-(1-{[trans-4-(7H-pyrrolo[3,2-e][1,2, colorless solid 59%3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}piperidin-4-yl)propan-2-ol

TABLE^(a) 31 Ex Compound Name Morphology Yield 312cis-2-[({[trans-4-(7H-pyrrolo[3,2-e][1, colorless solid 14%2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)methyl]cyclohexanol313 1-[({[trans-4-(7H-pyrrolo[3,2-e][1,2, colorless solid 47%3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)methyl]cyclohexanol314 3-(4-{[trans-4-(7H-pyrrolo[3,2-e][1,2, colorless solid 35%3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}piperazin-1-yl)propanenitrile 315 2-(4-{[trans-4-(7H-pyrrolo[3,2-e][1,2, colorlesssolid 35% 3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}piperazin-1-yl)ethanol 316 N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,colorless solid 44%5-c]pyrimidin-1-yl)cyclohexyl]methyl}bicyclo[1.1.1]pentan- 1-amine 317N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 77%5-c]pyrimidin-1-yl)cyclohexyl]methyl}- 1,1,1,3,3,3-hexafluoropropan-2-amine 318 N-((R)-1-{[trans-4-(7H-pyrrolo[3,2-e][1, colorless solid 48%2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}pyrrolidin-3-yl)acetamide 319 N-((S)-1-{[trans-4-(7H-pyrrolo[3,2-e][1, colorlesssolid 29%2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}pyrrolidin-3-yl)acetamide 320 N-((R)-1-{[trans-4-(7H-pyrrolo[3,2-e][1, colorlesssolid 49%2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}pyrrolidin- 3-yl)-2,2,2-trifluoroacetamide 321 N-((S)-1-{[trans-4-(7H-pyrrolo[3,2-e][1,colorless solid 48%2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}pyrrolidin- 3-yl)-2,2,2-trifluoroacetamide 322N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 52%5-c]pyrimidin-1-yl)cyclohexyl]methyl}- 3-(4-fluorophenyl)oxetan- 3-amine323 N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 39%5-c]pyrimidin-1-yl)cyclohexyl]methyl}-1-(4-fluorophenyl)cyclopropanamine

TABLE^(a) 32 Ex Compound Name Morphology Yield 324N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 39%5-c]pyrimidin-1-yl)cyclohexyl]methyl}- 1-(4-fluorophenyl)cyclobutanamine325 N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 71%5-c]pyrimidin-1-yl)cyclohexyl]methyl}- 2-methoxy-N-methylethanamine 326N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 76%5-c]pyrimidin-1-yl)cyclohexyl]methyl}-2-methoxy-N-(2-methoxyethyl)ethanamine 327[1-({[trans-4-(7H-pyrrolo[3,2-e][1,2, colorless solid 58%3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)cyclopropyl]methanol328 1-{trans-4-[(3,3-difluoropyrrolidin-1- colorless solid 26%yl)methyl]cyclohexyl}-7H-pyrrolo[3,2- e][1,2,3]triazolo[1,5-c]pyrimidine329 1-[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 26%5-c]pyrimidin-1-yl)cyclohexyl]- N-methylmethanamine 330N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 58%5-c]pyrimidin-1-yl)cyclohexyl]methyl}ethanamine 331N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 55%5-c]pyrimidin-1-yl)cyclohexyl]methyl}propan- 2-amine 332N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 34%5-c]pyrimidin-1-yl)cyclohexyl]methyl}- 2-methylpropan-2-amine 333N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 62%5-c]pyrimidin-1-yl)cyclohexyl]methyl}prop- 2-yn-1-amine 3344-(1-{[trans-4-(7H-pyrrolo[3,2-e][1,2, colorless solid 44%3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}piperidin-4-yl)morpholine 335 tert-butyl colorless solid 17%4-[({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)methyl]piperidine-1-carboxylate 336 tert-butyl colorless solid 3.0% [(1-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}piperidin-4-yl)methyl]carbamate

TABLE^(a) 33 Ex Compound Name Morphology Yield 337 (S)-tert-butylcolorless solid 10% 3-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)pyrrolidine- 1-carboxylate338 1-{trans-4-[(3-fluoroazetidin-1-yl)methyl]cyclohexyl}- colorlesssolid 33% 7H-pyrrolo[3,2-e][1, 2,3]triazolo[1,5-c]pyrimidine 3391-{trans-4-[(3,3-difluoroazetidin-1-yl)methyl]cyclohexyl}- colorlesssolid 35% 7H-pyrrolo[3,2-e][1, 2,3]triazolo[1,5-c]pyrimidine 340(R)-1-{[trans-4-(7H-pyrrolo[3,2-e][1, colorless solid 87%2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}-N,N-dimethylpyrrolidin- 3-amine 3412-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 63%5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)-N-(2,2,2-trifluoroethyl)acetamide 342N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 74%5-c]pyrimidin-1-yl)cyclohexyl]methyl}- 2,2,3,3,3-pentafluoropropan-1-amine 343 3-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorlesssolid 66% 5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)-1,1,1-trifluoropropan- 2-ol 344N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 58%5-c]pyrimidin-1-yl)cyclohexyl]methyl}thietan- 3-amine 3451-(trans-4-{[4-(ethylsulfonyl)piperazin- colorless solid 71%1-yl]methyl}cyclohexyl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

Synthetic Example^(a) 346trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)-N-(3,3,3-trifluoro-2-hydroxy-2-phenylpropyl)cyclohexanecarboxamide

trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanecarboxylicacid (10.0 mg, 0.0350 mmol) obtained in Synthetic Example^(a) 80 inN,N-dimethylformamide (1 mL) was mixed with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.10 mg,0.0420 mmol), 1-hydroxybenzotriazole (4.70 mg, 0.0350 mmol) and3-amino-1,1,1-trifluoro-2-phenylpropan-2-ol (7.20 mg, 0.0350 mmol)obtained in Reference Synthetic Example^(a) 101 and stirred at roomtemperature for one day. After addition of saturated aqueous ammoniumchloride, the reaction mixture was extracted with ethyl acetate, Theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel thinlayer chromatography (ethyl acetate/hexane=1/1(v/v)) to give the titlecompound as a colorless solid (5.80 mg, yield 35%).

Synthetic Example^(a) 347trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)-N-[3,3,3-trifluoro-2-(4-fluorophenyl)-2-hydroxypropyl]cyclohexanecarboxamide

The reactions in Synthetic Example^(a) 346 were carried out insubstantially the same manners except that3-amino-1,1,1-trifluoro-2-(4-fluorophenyl)propan-2-ol obtained inReference Synthetic Example^(a) 102 was used instead of3-amino-1,1,1-trifluoro-2-phenylpropan-2-ol to give the title compoundas a colorless solid (7.37 mg, yield 43%).

Synthetic Example^(a) 348 to 363

The reactions in Synthetic Example^(a) 206 were carried out insubstantially the same manners except that ammonium chloride,5-methylfurfurylamine, 4-(aminomethyl)benzonitrile hydrochloride,2-phenylglycinonitrile hydrochloride, 2-(4-chlorophenyl)ethylamine,(S)-2-amino-1-phenylethanol, 2,2,2-trifluoroethylamine hydrochloride,2-aminoacetonitrile hydrochloride, 3-aminopropionitrile,(S)-pyrrolidine-3-carbonitrile, (S)-pyrrolidine-3-ol, cyclopropylamine,2-aminoethanol, 3-hydroxyazetidine hydrochloride,4-(2-aminoethyl)benzonitrile or azetidine-3-carbonitrile hydrochloridewas used instead of 4-fluoroaniline to give the compounds of SyntheticExamples^(a) 348 to 363. The names, morphologies and yields of thesynthesized compounds are shown in Tables^(a) 34 to 35.

TABLE^(a) 34 Ex Compound Name Morphology Yield 348trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless 87%5-c]pyrimidin-1-yl)cyclohexanecarboxamide solid 349trans-N-[(5-methylfuran-2-yl)methyl]- colorless 69%4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, solid5-c]pyrimidin-1-yl)cyclohexanecarboxamide 350trans-N-(4-cyanobenzyl)-4-(7H-pyrrolo[3, colorless 57%2-e][1,2,3]triazolo[1,5-c]pyrimidin- solid 1-yl)cyclohexanecarboxamide351 trans-N-[cyano(phenyl)methyl]-4-(7H- colorless 58%pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]- solidpyrimidin-1-yl)cyclohexanecarboxamide 352trans-N-(4-chlorophenethyl)-4-(7H- pale yellow 68%pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]- solidpyrimidin-1-yl)cyclohexanecarboxamide 353trans-N-[(S)-2-hydroxy-2-phenylethyl]- colorless 40%4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, solid5-c]pyrimidin-1-yl)cyclohexanecarboamide

TABLE^(A) 35 Ex Compound Name Morphology Yield 354trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless 54%5-c]pyrimidin-1-yl)-N-(2,2,2-trifluoroethyl)- solidcyclohexanecarboxamide 355 trans-N-(cyanomethyl)-4-(7H-pyrrolo[3, palebrown 27% 2-e][1,2,3]triazolo[1,5-c]pyrimidin- solid1-yl)cyclohexanecarboxamide 356 trans-N-(2-cyanoethyl)-4-(7H-pyrrolo[3,colorless 29% 2-e][1,2,3]triazolo[1,5-c]pyrimidin- solid1-yl)cyclohexanecarboxamide 357 (S)-1-[trans-4-(7H-pyrrolo[3,2-e][1,2,colorless 17% 3]triazolo[1,5-c]pyrimidin-1-yl)- solidcyclohexanecarbonyl]- pyrrolidine-3-carbonitrile 358[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless 18%5-c]pyrimidin-1-yl)cyclohexyl][(S)- solid3-hydroxypyrrolidin-1-yl]methanone 359trans-N-cyclopropyl-4-(7H-pyrrolo[3,2- pale yellow 33%c][1,2,3]triazolo[1,5-c]pyrimidin-1- solid yl)cyclohexanecarboxamide 360trans-N-(2-hydroxyethyl)-4-(7H-pyrrolo[3, pale brown 15%2-e][1,2,3]triazolo[1,5-c]pyrimidin- solid 1-yl)cyclohexanecarboxamide361 [trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless 87%5-c]pyrimidin-1-yl)cyclohexyl](3- solid hydroxyazetidin-1-yl)methanone362 trans-N-(4-cyanophenethyl)-4-(7H-pyrrolo[3, colorless 12%2-e][1,2,3]triazolo[1,5-c]pyrimidin- solid 1-yl)cyclohexanecarboxamide363 1-[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo- colorless 20%[1,5-c]pyrimidin-1-yl)cyclohexanecarbonyl]- solidazetidine-3-carbonitrile

Synthetic Examples^(a) 364 to 366

The reactions in Synthetic Example^(a) 77 were carried out insubstantially the same manners except that sodium benzene sulfinate,sodium 4-fluorobenzenesulfinate or sodium cyclopropanesulfinate was usedinstead of sodium methanesulfinate to give the compounds of SyntheticExamples^(a) 364 to 366. The names, morphologies and yields of thesynthesized compounds are shown in Table^(a) 36.

TABLE^(A) 36 Ex Compound Name Morphology Yield 3641-{trans-4-[(phenylsulfonyl)methyl]- colorless solid 30%cyclohexyl-}-7H-pyrrolo[3,2-e][1,2,3]- triazolo[1,5-c]pyrimidine 3651-(trans-4-{[(4-fluorophenyl)sulfonyl]- colorless solid 36%methyl}cyclohexyl)-7H-pyrrolo[3,2-c][1, 2,3]triazolo[1,5-c]pyrimidine366 1-{trans-4-[(cyclopropylsulfonyl)methyl]- colorless solid 30%cyclohexyl}-7H-pyrrolo[3,2-e][1,2, 3]triazolo[1,5-c]pyrimidine

Synthetic Example^(a) 3671-[trans-4-(lodomethyl)cyclohexyl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

2,3-Dichloro-5,6-dicyano-p-benzoquinone (50.0 mg, 0.221 mmol) andtriphenylphosphine (58.0 mg, 0.221 mmol) in dichloromethane (3 mL) weremixed with tetrabutylammonium iodide (81.7 mg, 0.221 mmol) and[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methanol(50.0 mg, 0.184 mmol) obtained in Synthetic Example^(a) 10 and then wasstirred at 40° C. for 8 hours. After addition of water, the reactionmixture was extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(hexane/ethyl acetate=1/1→3/2 (v/v)) to give the title compound as acolorless solid (51.9 mg, yield 74%).

Synthetic Example^(a) 3681-(trans-4-{[(Trifluoromethyl)sulfonyl]methyl}cyclohexyl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

1-[trans-4-(lodomethyl)cyclohexyl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine(50.0 mg, 0.131 mmol) and sodium trifluoromethylsulfinate (205 mg, 1.31mmol) in N,N-dimethylformamide(3 mL) were stirred at 100° C. for 26hours. After addition of water, the reaction mixture was extracted withethyl acetate. The organic layer washed with saturated aqueous sodiumhydrogen carbonate, saturated aqueous ammonium chloride and saturatedaqueous sodium chloride, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=3/2→1/1(v/v)) andpreparative HPLC (Waters XBridge Prep C18 μm ODS, 19×100 mm,acetonitrile/0.1% aqueous formic acid solution=20/80→80/20(v/v)) to givethe title compound as a colorless solid (6.30 mg, yield 12%).

Synthetic Example^(a) 3691-[trans-4-(Azidomethyl)cyclohexyl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[,1,5-c]pyrimidine

1-[trans-4-(Bromomethyl)cyclohexyl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine(50.0 mg, 0.150 mmol) obtained in Synthetic Example^(a) 74 intetrahydrofurane (2 mL) was mixed with trimethylsilylazide (39.0 μL,0.299 mmol) and tetrabutylammonium fluoride-tetrahydrofuran solution (1M, 299 μL, 0.299 mmol) and then stirred at 50° C. for 3 hours. Afteraddition of water, the reaction mixture was extracted with ethylacetate. The organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was washed with ethyl acetate/hexane (1/5(v/v)) to give the title compound as a colorless solid (30.6 mg, yield69%).

Synthetic Example^(a) 3702-(1-{[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}-1H-1,2,3-triazol-4-yl)propan-2-ol

1-[trans-4-(Azidomethyl)cyclohexyl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine(30.0 mg, 0.101 mmol) and 2-methyl-3-butyn-2-ol (12.0 μL, 0.122 mmol) indichloromethane (3 mL) were mixed with copper(II) sulfate (24.0 mg,0.152 mmol) and sodium ascorbate (60.0 mg, 0.304 mmol) and then stirredat 80° C. for 2 hours. After addition of water, the reaction mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium hydrogen carbonate, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=4/1→0/1→ethyl acetate/methanol=20/1 (v/v)) to give the titlecompound as a colorless solid (13.2 mg, yield 34%).

Synthetic Example^(a) 371[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methanamine

1-[trans-4-(Azidomethyl)cyclohexyl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine(127 mg, 0.427 mmol) obtained in Synthetic Example^(a) 369 and 5%palladium-carbon (12.7 mg) in methanol (3 mL) and dichloromethane (3 mL)were stirred at room temperature for 4 hours under a hydrogenatmosphere. The reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/methanol=1/0→10/1 (v/v/) togive the title compound as a colorless solid (95.0 mg, yield 82%).

Synthetic Example^(a) 372N-{[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}-2-cyanoacetamide

[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methanamine(40.0 mg, 0.148 mmol), 2-cyanoacetic acid (15.0 mg, 0.178 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (68.0 mg, 0.178 mmol) in N,N-dimethylformamide (2mL) were mixed with N,N-diisopropylethylamine (57.0 μL, 0.326 mmol) andstirred at room temperature for 16 hours. After addition of water, thereaction mixture was extracted with ethyl acetate. The organic layer waswashed with saturated aqueous sodium hydrogen carbonate, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane/acetone=1/1→2/3 (v/v)) to give the title compound as a colorlesssolid (11.4 mg, yield 23%).

Synthetic Example^(a) 373N-{[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}-3,3,3-trifluoropropanamide

The reactions in Synthetic Example^(a) 372 were carried out insubstantially the same manners except that 3,3,3-trifluoropropanoic acidwas used instead of 2-cyanoacetic acid to give the title compound as acolorless solid (5.00 mg, yield 12%).

Synthetic Example^(a) 3741-{1-[(3-Chloro-5-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)methyl]piperidin-4-yl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

3-Chloro-5-methyl-1H-pyrazole-4-carbaldehyde (100 mg, 0.692 mmol) inN,N-dimethylformamide (2 mL) was mixed with potassium carbonate (287 mg,2.08 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (200 μL,1.38 mmol) and stirred at room temperature for 1 day. After addition ofsaturated aqueous ammonium chloride, the reaction mixture was extractedwith chloroform. The organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue and1-(piperidin-4-yl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidineacetate (20.0 mg, 0.0660 mmol) obtained in Reference SyntheticExample^(a) 104 were dissolved in methanol (1 mL) and mixed withnicotinic acid (12.3 mg, 0.0990 mmol) and 2-picoline borane (10.7 mg,0.0990 mmol). The reaction mixture was stirred at room temperature for 1day. After addition of 1 M aqueous sodium hydroxide, the reactionmixture was extracted with chloroform. The organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel thin layer chromatography(methanol/chloroform=1/10 (v/v)) to give the title compound as acolorless solid (2.35 mg, yield 8%).

Synthetic Example^(a) 3754-{2-[4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidin-1-yl]ethyl}benzonitrile

The reactions in Synthetic Example^(a) 32 were carried out insubstantially the same manners except that 4-cyanophenethyl4-methylbenzenesulfonate (Reference Synthetic Example^(a) 132) was usedinstead of benzyl bromide to give the title compound as a colorlesssolid (7.03 mg, yield 29%).

Synthetic Example^(a) 3764-[4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidin-1-yl]benzonitrile

1-(Piperidin-4-yl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidineacetate (30.0 mg, 0.0992 mmol) obtained in Reference SyntheticExample^(a) 104 in N,N-dimethylformamide (1 mL) was mixed with4-fluorobenzonitrile (18.0 mg, 0.149 mmol) and potassium carbonate (27.4mg, 0.198 mmol) and then stirred at 80° C. for 31 hours. After additionof water, the reaction mixture was extracted with chloroform. Theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel thinlayer chromatography (methanol/chloroform=1/19 (v/v)) to give the titlecompound as a colorless solid (0.520 mg, yield 2%).

Synthetic Example^(a) 3774-{[4-(9-Chloro-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidin-1-yl]methyl}benzonitrile

4-{[4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidin-1-yl]methyl}benzonitrile(20.0 mg, 0.0660 mmol) obtained in Synthetic Example^(a) 34 inN,N-dimethylformamide (1 mL) was mixed with N-chlorosuccinimide (10.7mg, 0.0990 mmol) and stirred at room temperature for 1 day. Afteraddition of 1M aqueous sodium hydroxide, the reaction mixture wasextracted with chloroform. The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by silica gel thin layer chromatography(methanol/chloroform=1/10 (v/v)) to give the title compound as acolorless solid (13.1 mg, yield 48%).

Synthetic Examples^(a) 378 to 380

The reactions in Synthetic Example^(a) 121 were carried out insubstantially the same manners except that(1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol,(1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol or3,3′-azanediyldipropanenitrile was used instead of 4-aminobenzonitrileto give cis/trans mixture of the compounds of Synthetic Examples^(a) 378to 380. The names, morphologies and yields of the compounds synthesizedare shown in Table^(a) 37.

TABLE^(A) 37 Ex Compound Name Morphology Yield 378(1R,2S)-1-{[4-(7H-pyrrolo[3,2-e][1,2, pale yellow 63%3]triazolo[1,5-c]pyrimidin-1-yl)- solidcyclohexyl]amino}-2,3-dihydro-1H-inden- 2-ol 379(1S,2R)-1-{[4-(7H-pyrrolo[3,2-e][1,2, pale yellow 78%3]triazolo[1,5-c]pyrimidin-1-yl)- solidcyclohexyl]amino}-2,3-dihydro-1H-inden- 2-ol 3803,3′-{[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless 22%5-c]pyrimidin-1-yl)cyclohexyl]azanediyl}- solid dipropanenitrile

Synthetic Examples^(a) 381 to 384

The reactions in Synthetic Example^(a) 136 were carried out insubstantially the same manners except that 4-fluoroaniline,2-bromo-2,2-difluoroethanamine hydrochloride (Reference SyntheticExample^(a) 131), 2,2,3,3,3-pentafluoropropylamine or2-amino-N-(2,2,2-trifluoroethyl)acetamide was used instead of3-phenylpropan-1-amine to give the compounds of Synthetic Examples^(a)381a to 384a in less polar fractions and the compounds of SyntheticExamples^(a) 381 b to 384b in more polar fractions. The names,morphologies and yields of the compounds synthesized are shown inTable^(a) 38.

TABLE^(a) 38 Mor- Ex Compound Name phology Yield 381aN-[cis-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, pale 11%5-c]pyrimidin-1-yl)cyclohexyl]- yellow 4-fluoroaniline solid 381bN-[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, pale 13%5-c]pyrimidin-1-yl)cyclohexyl]- yellow 4-fluoroaniline solid 382acis-N-(2-bromo-2,2-difluoroethyl)-4-(7H- colorless 1.0% pyrrolo[3,2-e][1,2,3]triazolo[1,5- solidc]pyrimidin-1-yl)cyclohexanamine 382btrans-N-(2-bromo-2,2-difluoroethyl)-4- colorless 4.0% (7H-pyrrolo[3,2-e][1,2,3]triazolo[1, solid5-c]pyrimidin-1-yl)cyclohexanamine 383acis-N-(2,2,3,3,3-pentafluoropropyl)-4- colorless 12%(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, solid5-c]pyrimidin-1-yl)cyclohexanamine 383btrans-N-(2,2,3,3,3-pentafluoropropyl)- colorless 29%4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, solid5-c]pyrimidin-1-yl)cyclohexanamine 384a2-{[cis-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless 11%5-c]pyrimidin-1-yl)cyclohexyl]amino}- solidN-(2,2,2-trifluoroethyl)acetamide 384b2-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless 27%5-c]pyrimidin-1-yl)cyclohexyl]amino}- solidN-(2,2,2-trifluoroethyl)acetamide

Synthetic Examples^(a) 385 to 400

The reactions in Synthetic Example^(a) 136 were carried out insubstantially the same manners except that3-amino-1,1,1-trifluoro-2-(pyridin-3-yl)propan-2-ol,3-amino-1,1,1-trifluoro-2-[4-(methylthio)phenyl]propan-2-ol,3-amino-1,1,1-trifluoro-2-(6-methoxypyridin-3-yl)propan-2-ol,3-amino-1,1,1-trifluoro-2-(4-methoxyphenyl)propan-2-ol,[trans-2-(4-fluorophenyl)cyclopropyl]methanamine,3-amino-2-(3,4-dimethoxyphenyl)-1,1,1-trifluoropropan-2-ol,4-(2-aminoethyl)benzonitrile, cyclopropylamine, 2-aminoacetonitrilehydrochloride, 3-aminopropanenitrile, 2,2,2-trifluoroethanaminehydrochloride, cyclopropylmethanamine, dimethylamine (2M solution intetrahydrofuran), methanamine (2M solution in methanol),2,2-difluoroethanamine or 1,1,1,3,3,3,-hexafluoropropan-2-amine was usedinstead of 3-phenylpropan-1-amine to give the compounds of SyntheticExamples^(a) 385b to 400b in more polar fractions. The names,morphologies and yields of the compounds synthesized are shown inTables^(a) 39 to 40.

TABLE^(a) 39 Ex Compound Name Morphology Yield 385b3-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 30%5-c]pyrimidin-1-yl)cyclohexyl]amino}- 1,1,1-trifluoro-2-(pyridin-3-yl)propan-2-ol 386b 3-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,colorless solid 31% 5-c]pyrimidin-1-yl)cyclohexyl]amino}-1,1,1-trifluoro-2-[4-(methylthio)phenyl]propan- 2-ol 387b3-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 26%5-c]pyrimidin-1-yl)cyclohexyl]amino}-1,1,1-trifluoro-2-(6-methoxypyridin- 3-yl)propan-2-ol 388b3-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 38%5-c]pyrimidin-1-yl)cyclohexyl]amino}-1,1,1-trifluoro-2-(4-methoxyphenyl)propan- 2-ol 389btrans-N-{[trans-2-(4-fluorophenyl)cyclopropyl]methyl}- colorless solid16% 4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanamine 390b3-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 12%5-c]pyrimidin-1-yl)cyclohexyl]amino}- 2-(3,4-dimethoxyphenyl)-1,1,1-trifluoropropan-2-ol 391b 4-(2-{[trans-4-(7H-pyrrolo[3,2-e][1,2,colorless solid 12%3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]amino}ethyl)benzonitrile 392btrans-N-cyclopropyl-4-(7H-pyrrolo[3,2- colorless solid 26%e][1,2,3]triazolo[1,5-c]pyrimidin-1- yl)cyclohexanamine 393b2-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, pale yellow 15%5-c]pyrimidin-1-yl)cyclohexyl]amino}acetonitrile solid 394b3-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, pale yellow 8.0% 5-c]pyrimidin-1-yl)cyclohexyl]amino}propanenitrile solid 395btrans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless solid 15%5-c]pyrimidin-1-yl)-N-(2,2,2-trifluoroethyl)cyclohexanamine 396btrans-N-(cyclopropylmethyl)-4-(7H-pyrrolo[3, pale brown solid 40%2-e][1,2,3]triazolo[1,5-c]pyrimidin- 1-yl)cyclohexanamine 397btrans-N,N-dimethyl-4-(7H-pyrrolo[3,2- pale yellow 27%e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanamine solid

TABLE^(a) 40 Ex Compound Name Morphology Yield 398btrans-N-methyl-4-(7H-pyrrolo[3,2-e][1, colorless 19%2,3]triazolo[1,5-c]pyrimidin-1- solid yl)cyclohexanamine 399btrans-N-(2,2-difluoroethyl)-4-(7H-pyrrolo[3, pale 20%2-e][1,2,3]triazolo[1,5-c]pyrimidin- yellow 1-yl)cyclohexanamine solid400b trans-N-(1,1,1,3,3,3-hexafluoropropan- colorless 7.0% 2-yl)-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, solid5-c]pyrimidin-1-yl)cyclohexanamine

Synthetic Example^(a) 401[cis-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methanol

The reactions in Synthetic Example^(a) 141 were carried out insubstantially the same manners except that1-(cis-4-{[(tert-butyldimethylsilyl)oxy]methyl}cyclohexyl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine(Reference Synthetic Example^(a) 135a) was used instead of1-(trans-4-{[(tert-butyldimethylsilyl)oxy]methyl}cyclohexyl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidineto give the title compound as a pale pink solid (297 mg, yield 57%).

Synthetic Example^(a) 402cis-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanecarbaldehyde

The reactions in Synthetic Example^(a) 78 were carried out insubstantially the same manners except that[cis-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methanolwas used instead of[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methanolto give the title compound as a colorless solid (192 mg, yield 88%).

Synthetic Example^(a) 4031-{[cis-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}azetidin-3-ol

cis-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanecarbaldehyde(30.0 mg, 0.111 mmol) in methanol (2 mL), tetrahydrofuran (1 mL) andacetic acid (100 μL) was mixed with 3-hydroxyazetidine hydrochloride(41.3 mg, 0.334 mmol) and stirred at room temperature for 1 hour. Thereaction mixture was mixed with 2-picoline borane (23.8 mg, 0.334 mmol)and stirred at room temperature for 14 hours. After addition of water,the reaction mixture was extracted with ethyl acetate. The aqueous layerwas adjusted to pH 10 with 1 M aqueous sodium hydroxide, and extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue was washedwith hexane/ethyl acetate (5/1 (v/v)) to give the title compound as acolorless solid (7.40 mg, yield 31%).

Synthetic Examples^(a) 404 to 406

The reactions in Synthetic Example^(a) 403 were carried out insubstantially the same manners except that (S)-pyrrolidin-3-olhydrochloride, (R)-pyrrolidin-3-ol hydrochloride or cyclopropylaminehydrochloride (Reference Synthetic Example^(a) 136) was used instead of3-hydroxyazetidine hydrochloride to give the compounds of SyntheticExamples^(a) 404 to 406. The names, morphologies and yields of thecompounds synthesized are shown in Table^(a) 41.

TABLE^(a) 41 Mor- Ex Compound Name phology Yield 404(S)-1-{[cis-4-(7H-pyrrolo[3,2-e][1,2, colorless 96%3]triazolo[1,5-c]pyrimidin-1- solid yl)cyclohexyl]methyl}pyrrolidin-3-ol405 (R)-1-{[cis-4-(7H-pyrrolo[3,2-e][1,2, colorless 55%3]triazolo[1,5-c]pyrimidin-1- solid yl)cyclohexyl]methyl}pyrrolidin-3-ol406 N-{[cis-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless 16%5-c]pyrimidin-1- solid yl)cyclohexyl]methyl}cyclopropanamine

Synthetic Example^(a) 407N-{[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}-2-cyano-N-(2,2,2-trifluoroethyl)acetamide

N-{[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}-2,2,2-trifluoroethanamine(20.0 mg, 0.0567 mmol) obtained in Synthetic Example^(a) 188 inN,N-dimethylformamide (1 mL) was mixed with 2-cyanoacetic acid (9.60 mg,0.113 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,NI, NI-tetramethyluroniumhexafluorophosphate (45.0 mg, 0.113 mmol) and stirred withN,N-diisopropylethylamine (0.0346 mL, 0.198 mmol) at room temperaturefor 2 hours. After addition of water, the reaction mixture was extractedwith ethyl acetate. The organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=1/1→6/1 (v/v)) to give the titlecompound as a colorless solid (23.6 mg, yield 99%).

Synthetic Examples^(a) 408 to 410

The reactions in Synthetic Example^(a) 407 were carried out insubstantially the same manners except that2-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)acetonitrile(Synthetic Example^(a) 259),N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}cyclopropanamine(Synthetic Example^(a) 280) or1-[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]-N-[(5-methylfuran-2-yl)methyl]methanamine(Synthetic Example^(a) 182) was used instead ofN-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}-2,2,2-trifluoroethanamineto give the compounds of Synthetic Examples^(a) 408 to 410. The names,morphologies and yields of the compounds synthesized are shown inTable^(a) 42.

TABLE^(a) 42 Ex Compound Name Morphology Yield 408N-{[trans-4-(7H-pyrrolo[3,2-e][1,2, colorless solid 53%3]triazolo[1,5-c]pyrimidin-1- yl)cyclohexyl]methyl}-2-cyano-N-(cyanomethyl)acetamide 409 N-{[trans-4-(7H-pyrrolo[3,2-e][1,2,colorless solid 93% 3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}-2- cyano-N-cyclopropylacetamide 410N-{[trans-4-(7H-pyrrolo[3,2-e][1,2, gray solid 83%3]triazolo[1,5-c]pyrimidin-1- yl)cyclohexyl]methyl}-2-cyano-N-[(5-methylfuran- 2-yl)methyl]acetamide

Synthetic Example^(a) 411N-{[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}-3,3,3-trifluoro-N-(2,2,2-trifluoroethyl)propanamide

The reactions in Synthetic Example^(a) 407 were carried out insubstantially the same manners except that 3,3,3-trifluoropropionic acidwas used instead of 2-cyanoacetic acid to give the title compound as acolorless solid (8.80 mg, yield 33%).

Synthetic Example^(a) 412N-{[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}-N-(cyanomethyl)-3,3,3-trifluoropropanamide

The reactions in Synthetic Example^(a) 411 were carried out insubstantially the same manners except that2-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)acetonitrile(Synthetic Example^(a) 259) was used instead ofN-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}-2,2,2-trifluoroethanamineto give the title compound as a colorless solid (6.40 mg, yield 64%).

Synthetic Example^(a) 413trans-N-(Cyclopropylmethyl)-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)-N-(2,2,2-trifluoroethyl)cyclohexanamine

trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)-N-(2,2,2-trifluoroethyl)cyclohexanamine(5.00 mg, 0.0148 mmol) obtained in Synthetic Example′ 395 in methanol (1mL) and acetic acid (0.1 mL) was mixed with cyclopropanecarbaldehyde(1.60 μL, 0.0222 mmol) and 2-picoline borane (2.30 mg, 0.0222 mmol) andstirred at room temperature for 1 day. After addition of 1 M aqueoussodium hydroxide, the reaction mixture was extracted with ethyl acetate.The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane=1/3→1/1 (v/v)) to givethe title compound as a colorless solid (4.00 mg, yield 70%).

Synthetic Examples^(a) 414 and 415

The reactions in Synthetic Example^(a) 413 were carried out insubstantially the same manners except that2-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)acetonitrile(Synthetic Example^(a) 259) orN-{[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}-2,2,2-trifluoroethanamine(Synthetic Example^(a) 188) was used instead oftrans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)-N-(2,2,2-trifluoroethyl)cyclohexanamineto give the compounds of Synthetic Examples^(a) 414 and 415. The names,morphologies and yields of the compounds synthesized are shown inTable^(a) 43.

TABLE^(a) 43 Ex Compound Name Morphology Yield 4142-({[trans-4-(7H-pyrrolo[3,2- colorless 73%e][1,2,3]triazolo[1,5-c]pyrimidin-1- yl)cyclohexyl]methyl} solid(cyclopropylmethyl)amino)acetonitrile 415 N-{[trans-4-(7H-pyrrolo[3,2-colorless 78% e][1,2,3]triazolo[1, 5-c]pyrimidin-1-yl)cyclohexyl]methyl}- solid N-(cyclopropylmethyl)-2,2,2-trifluoroethanamine

Synthetic Example^(a) 416[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methanesulfonicacid

S-[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methylethanethioate (127 mg, 0.390 mmol) obtained in Synthetic Example^(a) 71in methanol (4 mL) was mixed with ammonium molybdate tetrahydrate (145mg, 0.117 mmol) and hydrogen peroxide solution (0.63 mL, 7.80 mmol) andstirred at room temperature for 1 day. The reaction mixture was mixedwith saturated aqueous sodium thiosulfate, concentrated under reducedpressure and purified by silica gel column chromatography (ethylacetate/methanol=4/1→1/1 (v/v)). The resulting solid was mixed withwater and extracted with n-butanol. The organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure to givethe title compound as a pale yellow solid (39.8 mg, yield 28%).

Synthetic Example^(a) 4171-[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]-N-cyclopropylmethanesulfonamide

[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methanesulfonicacid (17.8 mg, 0.0530 mmol) in dichloromethane (1.5 mL) andN,N-dimethylformamide (1.8 mL) was stirred with thionyl chloride(0.00770 mL, 0.106 mmol) at room temperature for 1 hour. The reactionmixture was concentrated under reduced pressure. The residue wasdissolved in dichloromethane (1.0 mL) and mixed withN,N-diisopropylethylamine (0.0923 mL, 0.530 mmol) and cyclopropylamine(0.0148 mL, 0.212 mmol) under cooling with ice and then stirred at roomtemperature for 1 day. After addition of water, the reaction mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium chloride, dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl hexane/acetate=4/1→1/1→1/3(v/v)) to give the title compound as a brown solid (1.50 mg, yield7.5%).

Synthetic Examples^(a) 418 to 420

The reactions in Synthetic Example^(a) 417 were carried out insubstantially the same manners except that dimethylamine hydrochloride,2-aminoacetonitrile hydrochloride or 2,2,2-trifluoroethanaminehydrochloride was used instead of cyclopropylamine to give the compoundsof Synthetic Examples^(a) 418 to 420. The names, morphologies and yieldsof the compounds synthesized are shown in Table^(a) 44.

TABLE^(a) 44 Ex Compound Name Morphology Yield 4181-[trans-4-(7H-pyrrolo[3,2-e][1,2, colorless 15%3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]- solidN,N-dimethylmethanesulfonamide 419 1-[trans-4-(7H-pyrrolo[3,2-e][1,2,yellow solid 12% 3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]-N-(cyanomethyl)methanesulfonamide 420 1-[trans-4-(7H-pyrrolo[3,2-e][1,2,pale yellow 5.0%  3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]- solidN-(2,2,2-trifluoroethyl)methanesulfonamide

Synthetic Example^(a) 4211-(trans-4-{[3-(2,2,2-Trifluoroethoxy)azetidin-1-yl]methyl}cyclohexyl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

tert-Butyl 3-(2,2,2-trifluoroethoxy)azetidine-1-carboxylate (350 mg,1.37 mmol) obtained in Reference Synthetic Example^(a) 116 in ethylacetate (1 mL) was mixed with 4 M hydrogen chloride-1,4-dioxane solution(3 mL) under cooling with ice and then stirred at room temperature for 2hours. The reaction mixture was concentrated to give a colorless oil(224 mg). The resulting colorless oil (64.0 mg) was dissolved inmethanol (2 mL), tetrahydrofuran (1 mL) and acetic acid (100 μL) andstirred withtrans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanecarbaldehyde(30.0 mg, 0.111 mmol) obtained in Synthetic Example^(a) 78 at roomtemperature for 1 hour. The reaction mixture was mixed with 2-picolineborane (23.8 mg, 0.334 mmol) and stirred at room temperature for 14hours. After addition of water, the reaction mixture was extracted withethyl acetate. The aqueous layer was adjusted to pH 10 with 1 M aqueoussodium hydroxide, and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was washed with hexane/ethyl acetate (5/1 (v/v))to give the title compound as a light purple solid (14.9 mg, yield 33%).

Synthetic Examples^(a) 422 to 424

The reactions in Synthetic Example^(a) 421 were carried out insubstantially the same manners except that tert-butyl3-hydroxy-3-methylazetidine-1-carboxylate (Reference SyntheticExample^(a) 113), tert-butyl 3-(dimethylamino)azetidine-1-carboxylate(Reference Synthetic Example^(a) 137) or tert-butyl3-[ethyl(methyl)amino]azetidine-1-carboxylate (Reference SyntheticExample^(a) 138) was used instead of tert-butyl3-(2,2,2-trifluoroethoxy)azetidine-1-carboxylate to give the compoundsof Synthetic Examples^(a) 422 to 424. The names, morphologies and yieldsof the compounds synthesized are shown in Table^(a) 45.

TABLE^(a) 45 Ex Compound Name Morphology Yield 4221-{[trans-4-(7H-pyrrolo[3,2-c][1,2, colorless solid 21%3]triazolo[1,5-c]pyrimidin-1- yl)cyclohexyl]methyl}-3-methylazetidin-3-ol 423 1-{[trans-4-(7H-pyrrolo[3,2-e][1,2, colorlesssolid 25% 3]triazolo[1,5-c]pyrimidin-1- yl)cyclohexyl]methyl}-N,N-dimethylazetidin-3-amine 424 1-{[trans-4-(7H-pyrrolo[3,2-e][1,2,colorless solid 34% 3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}-N-ethyl-N- methylazetidin-3-amine

Synthetic Example^(a) 4251-{[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}-3-(trifluoromethyl)azetidin-3-ol

The reactions in Synthetic Example^(a) 88 were carried out insubstantially the same manners except that3-(trifluoromethyl)azetidin-3-ol hydrochloride (Reference SyntheticExample^(a) 115) was used instead of thiomorpholine 1,1-dioxide to givethe title compound as a colorless solid (11.9 mg, yield 27%).

Synthetic Example^(a) 4261-{[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}-N-(2,2,2-trifluoroethyl)azetidine-3-carboxamide

1-{[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}azetidine-3-carboxylicacid (40.0 mg, 0.113 mmol) obtained in Synthetic Example^(a) 278 and2,2,2-trifluoroethanamine hydrochloride (19.9 mg, 0.147 mmol) inN,N-dimethylformamide (2 mL) were mixed with N,N-diisopropylethylamine(74.9 μL, 0.440 mmol) and(1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphate (62.8 mg, 0.147 mmol) and stirred at roomtemperature for 1 day. After addition of saturated aqueous sodiumhydrogen carbonate, the reaction mixture was extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was washed withhexane/chloroform (3/1 (v/v)) to give the title compound as a paleyellow solid (5.40 mg, yield 11%).

Synthetic Example^(a) 427N-{[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}methanesulfonamide

[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methanamine(20.0 mg, 0.0740 mmol) obtained in Synthetic Example^(a) 371 indichloromethane (2 mL) was mixed with methanesulfonyl chloride (13.8 μL,0.0814 mmol) under cooling with ice and then stirred at room temperaturefor 65 hours. After addition of water, the reaction mixture wasextracted with ethyl acetate. The aqueous layer was washed with 1 Mhydrochloric acid and saturated aqueous ammonium chloride, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was washed with chloroform/hexane (1/5 (v/v)) to give the titlecompound as a colorless solid (6.00 mg, yield 23%).

Synthetic Example^(a) 428 tert-Butyl3-({[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}amino)-3-(cyanomethyl)azetidine-1-carboxylate

[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methanamine(11.2 mg, 0.0414 mmol) obtained in Synthetic Example^(a) 371 andtert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (10.4 mg, 0.0535mmol) obtained in Reference Synthetic Example^(a) 139 in acetonitrile (2mL) were mixed with 1,8-diazabicyclo[5.4.0]undec-7-ene (12.0 μL, 0.0535mmol) and stirred at room temperature for 1 day. After addition ofwater, the reaction mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodium chloride, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (NH-silicagel manufactured by Fuji Silysia Chemical Ltd.; chloroform/methanol=20/1(v/v)) to give the title compound as a pale yellow solid (14.2 mg, yield74%).

Synthetic Example^(a) 4294-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanecarbaldehydeoxime

[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexylcarbaldehyde(60.0 mg, 0.223 mmol) obtained in Synthetic Example^(a) 78 in methanol(1 mL) and water (1 mL) was mixed with hydroxylamine hydrochloride (31.0mg, 0.446 mmol) and sodium hydrogen carbonate (37.4 mg, 0.446 mmol) andthen stirred at 50° C. for 5 hours. The reaction mixture was filtered,and the resulting solid washed with water, water/methanol (10/1 (v/v))and hexane to give the title compound as a colorless solid (44.6 mg,yield 70%).

Synthetic Example^(a) 430trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanecarbonitrile

trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanecarbaldehydeoxime (37.4 mg, 0.132 mmol) in dichloromethane (3 mL) was mixed withtrifluoromethanesulfonic anhydride (24.0 μL, 0.145 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (43.0 μL, 0.289 mmol) and stirred atroom temperature for 18 hours. After addition of water, the reactionmixture was extracted with ethyl acetate. The organic layer was washedwith saturated aqueous sodium hydrogen carbonate, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (hexane/ethylacetate=3/2 (v/v)) and washed with hexane/ethyl acetate (5/1 (v/v)) togive the title compound as a colorless solid (20.7 mg, yield 59%).

Synthetic Example^(a) 4312-{[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methylene}malononitrile

trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexylcarbaldehyde(50.0 mg, 0.186 mmol) obtained in Synthetic Example^(a) 78 andmalononitrile (24.5 mg, 0.371 mmol) were mixed with acetic acid (3 mL),piperidine (18.3 μL, 0.186 mmol) and dichloromethane (2 mL) undercooling with ice and stirred for 1 hours. The reaction mixture was mixedanhydrous sodium sulfate and then stirred room temperature for 17 hours.After addition of water, the reaction mixture was extracted with ethylacetate. The organic layer was washed with saturated aqueous sodiumhydrogen carbonate, dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/acetone=2/1→3/2 (v/v)) to give the title compoundas a colorless solid (36.3 mg, yield 62%).

Synthetic Example^(a) 4322-{[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methyl}malononitrile

2-{[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methylene}malononitrile(25.8 mg, 0.0812 mmol) in tetrahydrofuran (3 mL) was mixed with diethyl1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (30.8 mg, 0.122 mmol)and stirred at room temperature for 1 hours. After addition of water,the reaction mixture was extracted with ethyl acetate. The organic layerwas washed with saturated aqueous ammonium chloride, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=1/1→1/2→0/1 (v/v)) to give the title compound as a colorlesssolid (14.2 mg, yield 55%).

Synthetic Example^(a) 4331-(4-Methylenecyclohexyl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine

1-[trans-4-(lodomethyl)cyclohexyl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine(15.0 mg, 0.0393 mmol) obtained in Synthetic Example^(a) 367 intetrahydrofuran (1 mL) was mixed with (trifluoromethyl)trimethysilane(7.60 μL, 0.0512 mmol) and tetrabutylammonium fluoride tetrahydrofuransolution (1 M, 51.2 μL, 0.0512 mmol) under cooling with ice and thenstirred at room temperature for 2 days. The reaction mixture was mixedwith water, and the precipitate was collected by filtration. Theresulting residue was purified by silica gel thin layer chromatography(ethyl acetate/hexane=1/1 (v/v)) to give the title compound as acolorless solid (3.80 mg, yield 38%).

Synthetic Example^(a) 4342-[4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexylidene]acetonitrile

Diethyl(cyanomethyl)phosphonate (37.0 μL, 0.235 mmol) in tetrahydrofuran(1 mL) was mixed with sodium hydride (55 wt % dispersion in mineral oil,10.0 mg, 0.235 mmol) under cooling with ice and then stirred for 30minutes. The reaction mixture was mixed with4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanone(20.0 mg, 0.0783 mmol) obtained in Synthetic Example^(a) 82 and thenstirred at room temperature for 30 minutes. After addition of water, thereaction mixture was extracted with ethyl acetate. The organic layer waswashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethylacetate/hexane=1/2→1/1→1/0 (v/v)) to give the title compound as acolorless solid (20.0 mg, yield 92%).

Synthetic Example^(a) 435 435a:2-[cis-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]acetonitrile435b:2-[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]acetonitrile

2-[4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexylidene]acetonitrile(20.0 g, 0.0720 mmol) in tetrahydrofuran (10 mL) were stirred with 5%palladium-carbon (10 mg) at room temperature for 4 hours under ahydrogen atmosphere. The reaction mixture was filtered, and the filtratewas concentrated under reduced pressure. The residue was purified bysilica gel thin layer chromatography (hexane/ethyl acetate=1/1 (v/v)) togive2-[cis-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]acetonitrile(Synthetic Example^(a) 435a; colorless solid, 1.30 mg, yield 6%) in aless polar fraction and2-[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]acetonitrile(Synthetic Example^(a) 435b; colorless solid, 3.40 mg, yield 17%) in amore polar fraction.

Synthetic Examples^(a) 436 and 437

The reactions in Synthetic Example^(a) 434 were carried out insubstantially the same manners except that ethyl 2-(diethoxyphosphoryl)acetate or diethyl(1-cyanoethyl)phosphonate was used instead ofdiethyl(cyanomethyl)phosphonate to give the compounds of SyntheticExamples^(a) 436 and 437. The names, morphologies and yields of thecompounds synthesized are shown in Table^(a) 46.

TABLE^(a) 46 Ex Compound Name Morphology Yield 436 ethyl colorless 94%2-[4-(7H-pyrrolo[3,2-c][1,2,3]triazolo[1, solid5-c]pyrimidin-1-yl)cyclohexylidene]acetate 4372-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1, colorless 41% 5-c]pyrimidin-1-solid yl)cyclohexylidene]propanenitrile

Synthetic Example^(a) 438 Ethyl2-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]acetate

The reactions in Synthetic Example^(a) 435 were carried out insubstantially the same manners except that ethyl2-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexylidene]acetateobtained in Synthetic Example^(a) 436 was used instead of2-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexylidene]acetonitrileto give the title compound as a colorless solid (cis/trans mixture; 29.0mg, yield 51%).

Synthetic Example^(a) 439 439a:2-[cis-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]propanenitrile439b:2-[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]propanenitrile

The reactions in Synthetic Example^(a) 435 were carried out insubstantially the same manners except that2-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexylidene]propanenitrileobtained in Synthetic Example^(a) 437 was used instead of2-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexylidene]acetonitrileto give2-[cis-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]propanenitrile(Synthetic Example^(a) 439a; colorless solid, 0.750 mg, yield 7%) in aless polar fraction and2-[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]propanenitrile(Synthetic Example^(a) 439 b; colorless solid, 2.00 mg, yield 19%) in amore polar fraction.

Synthetic Example^(a) 440(E)-3-[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]acrylonitrile

The reactions in Synthetic Example^(a) 434 were carried out insubstantially the same manners except thattrans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanecarbaldehyde(30.0 mg, 0.111 mmol) obtained in Synthetic Example^(a) 78 was usedinstead of4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanoneto give the title compound as a colorless solid (3.60 mg, yield 7%).

Synthetic Example^(a) 4413-[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]propanenitrile

The reactions in Synthetic Example^(a) 438 were carried out insubstantially the same manners except that(E)-3-[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]acrylonitrileobtained in Synthetic Example^(a) 440 was used instead of ethyl2-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexylidene]acetateto give the title compound as a colorless solid (7.30 mg, yield 72%).

Synthetic Example^(a) 442 442a:2-[cis-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]-N-2,2,2-trifluoroethylacetamide442b:2-[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]-N-2,2,2-trifluoroethylacetamide

Ethyl2-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]acetate(10.0 mg, 0.0305 mmol) obtained in Synthetic Example^(a) 438 intetrahydrofuran (1 mL) was mixed with ethanol (0.5 mL), water (0.25 mL)and 1 M aqueous lithium hydroxide (60 μL, 0.0611 mmol) and stirred atroom temperature for 4 hours. The reaction mixture was mixed with 1 Mhydrochloric acid and concentrated under reduced pressure. The residuewas dissolved in N,N-dimethylformamide (2 mL) and stirred withO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (23.2 mg, 0.0610 mmol), N,N-diisopropylethylamine(21.0 μL, 0.122 mmol) and 2,2,2-trifluoroethanamine hydrochloride (8.30mg, 0.0610 mmol) at room temperature for 13 hours. After addition ofsaturated aqueous ammonium chloride, the reaction mixture was extractedwith ethyl acetate. The organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel thinlayer chromatography (ethyl acetate) to give2-[cis-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]-N-(2,2,2-trifluoroethyl)acetamide(Synthetic Example^(a) 442a; colorless solid, 5.80 mg, yield 50%) in aless polar fraction and2-[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]-N-(2,2,2-trifluoroethyl)acetamide(Synthetic Example^(a) 442b; colorless solid, 3.10 mg, yield 27%) in amore polar fraction.

Synthetic Example^(a) 443 443a:2-[cis-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]-N-(cyanomethyl)acetamide443b:2-[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]-N-(cyanomethyl)acetamide

The reactions in Synthetic Example^(a) 442 were carried out insubstantially the same manners except that 2-aminoacetonitrilehydrochloride was used instead of 2,2,2-trifluoroethanaminehydrochloride to give2-[cis-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]-N-(cyanomethyl)acetamide(Synthetic Example^(a) 443a; pale brown solid, 7.00 mg, yield 47%) in aless polar fraction and2-[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]-N-(cyanomethyl)acetamide(Synthetic Example^(a) 443b; pale brown solid, 3.80 mg, yield 25%) in amore polar fraction.

Synthetic Example^(a) 4446-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)spiro[2.5]octane-1-carbonitrile

Trimethylsulfonium iodide (59.0 μL, 0.269 mmol) in dimethyl sulfoxide (1mL) was stirred with sodium hydride (55 wt % dispersion in mineral oil,12.0 mg, 0.269 mmol) at room temperature for 30 minutes. The reactionmixture was mixed with2-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexylidene]acetonitrile(15.0 mg, 0.0539 mmol) obtained in Synthetic Example^(a) 434 and thenstirred at room temperature for 15 hours. After addition of water, thereaction mixture was extracted with ethyl acetate. The organic layer waswashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethylacetate/hexane=1/1 (v/v)) to give the title compound as a colorlesssolid (5.80 mg, yield 37%).

Synthetic Example^(a) 4453-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)adamantan-1-ol

(3-Hydroxyadamantan-1-yl)(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone(22.5 mg, 0.0757 mmol) obtained in Reference Synthetic Example^(a) 141in methanol (1.5 mL) was mixed with hydrazine hydrate (0.141 mL, 2.27mmol) and then stirred at 80° C. for 2 hours. The reaction mixture wasmixed with hydrazine hydrate (0.118 mL, 1.89 mmol) and acetic acid (1drop) and stirred at 80° C. for 2 hours. The reaction mixture was mixedwith ethyl acetate, washed with water and saturated sodium chloride. Theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was dissolved in chloroform (1.5 mL)and mixed with manganese(IV) oxide (32.9 mg, 0.379 mmol). The reactionmixture was stirred at 70° C. for 6 hours. The reaction mixture wasfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel thin layer chromatography (ethylacetate) and further by silica gel thin layer chromatography (NH-PLC05plate manufactured by Fuji Silysia Chemical Ltd.: ethylacetate/hexane=15/1) to give the title compound as a colorless solid(3.30 mg, yield 14%).

The structural formulae of the compounds obtained the ReferenceSynthetic Examples^(a) and Synthetic Examples^(a) are shown below inTables^(a) 47 to 80. The physical property data on the compoundsobtained the Reference Synthetic Examples' and Synthetic Examples^(a)are shown below in Tables^(a) 81 to 151.

TABLE^(a) 47 Rf Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE^(a) 48 Rf Structure 25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

TABLE^(a) 49 Rf Structure 46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

TABLE^(a) 50 Rf Structure 70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

TABLE^(a) 51 Rf Structure 88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

TABLE^(a) 52 Rf Structure 105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128a

128b

129

130

131

132

133

TABLE^(a) 53 Rf Structure 134

135a

135b

136

137

138

139

140

141

TABLE^(a) 54 Ex Structure 1

2

3

  racemate 4

  racemate 5

6

7

  diastereomixture 8

9

10

TABLE^(a) 55 Ex Structure 11

  diastereomixture 12

  diastereomixture 13

  racemate 14

  racemate 15

  racemate 16

  racemate 17

  racemate 18

  racemate 19

  racemate 20

  racemate 21

  racemate 22

  racemate 23

  racemate 24

25

26

27

28

TABLE^(a) 56 Ex Structure 29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

TABLE^(a) 57 Ex Structure 47

48

49

50

51

52

53

54

55

56a

  less polar fraction 56b

  less polar fraction 57

58

59

60

61

62

63

TABLE^(a) 58 Ex Structure 64

65

  diastereomixture 66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

TABLE^(a) 59 Ex Structure 82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

TABLE^(a) 60 Ex Structure 100

101

102

103

104

105

106

107

108

109

  racemate 110

111

112

113

114

115

116

117

TABLE^(a) 61 Ex Structure 118

119

120

121

  cis/trans mixture 122

  cis/trans mixture 123

  cis/trans mixture 124

  cis/trans mixture 125

  cis/trans mixture 126

  cis/trans mixture 127

  cis/trans mixture 128

  cis/trans mixture 129

  cis/trans mixture 130

  cis/trans mixture 131

  cis/trans mixture 132

  cis/trans mixture 133

  cis/trans mixture 134a

134b

TABLE^(a) 62 Ex Structure 135a

135b

136a

136b

137a

137b

138a

138b

139a

139b

140

141

142

143

144

145

146

147

TABLE^(a) 63 Ex Structure 148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

TABLE^(a) 64 Ex Structure 166

167

168

169

170

171

172

  racemate 173

174

175

176

177

178

179

180

181

182

183

TABLE^(a) 65 Ex Structure 184

185

186

  racemate 187

188

189

190

191

192

193

194a

194b

195a

195b

196a

  racemate 196b

  racemate 197a

197b

TABLE^(a) 66 Ex Structure 198b

199b

  racemate 200b

  racemate 201b

202b

  racemate 203b

204b

205

  cis/trans mixture 206

207

208

209

210

211

  racemate 212

  racemate

TABLE^(a) 67 Ex Structure 213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

TABLE^(a) 68 Ex Structure 231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

  racemate 246

247

248

TABLE^(a) 69 Ex Structure 249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

TABLE^(a) 70 Ex Structure 267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

TABLE^(a) 71 Ex Structure 285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

TABLE^(a) 72 Ex Structure 303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

TABLE^(a) 73 Ex Structure 321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

TABLE^(a) 74 Ex Structure 339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

TABLE^(a) 75 Ex Structure 357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

TABLE^(a) 76 Ex Structure 375

376

377

378

379

380

381a

381b

382a

382b

383a

383b

384a

384b

385b

386b

387b

388b

TABLE^(a) 77 Ex Structure 389b

390b

391b

392b

393b

394b

395b

396b

397b

398b

399b

400b

401

402

403

404

405

406

TABLE^(a) 78 Ex Structure 407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

TABLE^(a) 79 Ex Structure 425

426

427

428

429

430

431

432

433

434

435a

435b

436

437

438

439a

439b

440

TABLE^(a) 80 Ex Structure 441

442a

442b

443a

443b

444

445

TABLE^(a) 81 Rf Data 1 ¹H-NMR (DMSO-d₆) δ: 6.63 (d, J = 2.6 Hz, 1H),7.67 (t, J = 2.6 Hz, 1H), 8.44 (s, 1H). LC/MS: condition 1, retentiontime = 2.61 min LC/MS (ESI⁺) m/z; 246 [M + H]⁺ LC/MS (ESI⁻) m/z; 244 [M− H]⁻ 2 ¹H-NMR (CDCl₃) δ: 1.11 (d, J = 7.2 Hz, 18H), 1.79-1.89 (m, 3H),6.46 (d, J = 3.3 Hz, 1H), 7.31 (d, J = 3.6 Hz, 1H), 8.47 (s, 1H). LC/MS:condition 1, retention time = 5.97 min LC/MS (ESI⁺) m/z; 402 [M + H]⁺ 3LC/MS: condition 1, retention time = 4.91 min LC/MS (ESI⁺) m/z; 388 [M +H]⁺ 4 LC/MS: condition 1, retention time = 4.05 min LC/MS (ESI⁺) m/z;230 [M − TIPS]⁺ 5 ¹H-NMR (CD₃OD) δ: 1.46 (dd, J = 18.8, 9.5 Hz, 4H),1.70-2.00 (m, 6H), 3.90-4.00 (m, 1H), 7.08 (d, J = 3.6 Hz, 1H), 7.63 (d,J = 3.6 Hz, 1H), 8.88 (s, 1H). LC/MS: condition 1, retention time = 4.02min LC/MS (ESI⁺) m/z; 230 [M + H]⁺ LC/MS (ESI⁻) m/z; 228 [M − H]⁻ 6¹H-NMR (CDCl₃) δ: −0.06 (s, 9H), 0.81-0.97 (m, 2H), 1.19-1.60 (m, 5H),1.69-2.07 (m, 5H), 3.45-3.58 (m, 2H), 3.86-4.03 (m, 1H), 5.68 (s, 2H),7.18-7.26 (m, 1H), 7.51 (d, J = 3.6 Hz, 1H), 9.01 (s, 1H). LC/MS:condition 1, retention time = 5.59 min LC/MS (ESI⁺) m/z; 360 [M + H]⁺ 7LC/MS: condition 1, retention time = 3.39 min LC/MS (ESI⁺) m/z; 361 [M +H]⁺ 8 LC/MS: condition 1, retention time = 4.54 min LC/MS (ESI⁺) m/z;371 [M + 1]⁺ 9 ¹H-NMR (CDCl₃) δ: 2.34 (s, 3H), 3.30 (s, 3H), 3.53 (br s,3H), 7.12-7.22 (m, 3H), 7.27-7.39 (m, 1H). LC/MS: condition 1, retentiontime = 2.94 min LC/MS (ESI⁺) m/z; 180 [M + H]⁺ 10 ¹H-NMR (CDCl₃) δ: 2.46(s, 3H), 7.02-7.10 (m, 1H), 7.21-7.39 (m, 2H), 7.40-7.48 (m, 1H),7.50-7.58 (m, 2H), 9.01 (s, 1H), 9.49 (br s, 1H). LC/MS: condition 1,retention time = 3.59 min LC/MS (ESI⁺) m/z; 238 [M + H]⁺ LC/MS (ESI⁻)m/z; 236 [M − H]⁻ 11 ¹H-NMR (CDCl₃) δ: 1.15-1.58 (m, 5H), 1.61-1.90 (m,5H), 2.58-2.78 (m, 1H), 3.17 (s, 3H), 3.69 (s, 3H). LC/MS: condition 1,retention time = 3.47 min LC/MS (ESI⁺) m/z; 172 [M + H]⁺ 12 ¹H-NMR(CDCl₃) δ: 1.19-1.60 (m, 5H), 1.68-2.10 (m, 5H), 3.85-4.07 (m, 1H),7.19-7.25 (m, 1H), 7.45-7.58 (m, 1H), 9.00 (s, 1H), 9.43 (br s, 1H).LC/MS: condition 1, retention time = 4.05 min LC/MS (ESI⁺) m/z; 230 [M +H]⁺ LC/MS (ESI⁻) m/z; 228 [M − H]⁻

TABLE^(a) 82 Rf Data 13 ¹H-NMR (CDCl₃) δ: 0.91 (s, 1.5H), 0.94 (s,1.5H), 1.21-1.91 (m, 8H), 2.00-2.19 (m, 1H), 2.80-2.94 (m, 1H), 3.17 (s,3H), 3.68 (s, 3H). LC/MS: condition 1, retention time = 3.84 min LC/MS(ESI⁺) m/z; 186 [M + H]⁺ 14 ¹H-NMR (CDCl₃) δ: 0.77-0.86 (m, 3H),1.20-2.00 (m, 8H), 2.31-2.50 (m, 1H), 4.10-4.20 (m, 1H), 7.17-7.22 (m,1H), 7.43-7.52 (m, 1H), 8.98 (s, 1H), 9.18 (br s, 1H). LC/MS: condition1, retention time = 4.22 min LC/MS (ESI⁺) m/z; 244 [M + H]⁺ LC/MS (ESI⁻)m/z; 242 [M − H]⁻ 15 LC/MS: condition 2, retention time = 4.17 min LC/MS(ESI⁺) m/z; 376 [M + H]⁺ 16 ¹H-NMR (CDCl₃) δ: 1.10-1.90 (m, 5H),2.73-3.20 (m, 2H), 3.50 (t, J = 6.0 Hz, 2H), 3.65-4.15 (m, 2H), 5.13 (brs, 2H), 7.22-7.41 (m, 5H). 17 LC/MS: condition 1, retention time = 3.89min LC/MS (ESI⁺) m/z; 307 [M + H]⁺ 18 LC/MS: condition 1, retention time= 5.34 min LC/MS (ESI⁺) m/z; 495 [M + H]⁺ 19 LC/MS: condition 2,retention time = 3.77 min LC/MS (ESI⁺) m/z; 496 [M + H]⁺ 20 LC/MS:condition 1, retention time = 4.87 min LC/MS (ESI⁺) m/z; 506 [M + H]⁺ 21¹H-NMR (CDCl₃) δ: 0.93-1.13 (m, 2H), 1.20-1.32 (m, 1H), 1.44-1.65 (m,2H), 1.78-1.93 (m, 4H), 2.56-2.74 (m, 1H), 3.18 (s, 3H), 3.48 (t, J =6.0 Hz, 2H), 3.69 (s, 3H). LC/MS: condition 1, retention time = 1.22 minLC/MS (ESI⁺) m/z; 202 [M + H]⁺ 22 ¹H-NMR (CDCl₃) δ: 1.05 (s, 9H),1.40-1.68 (m, 5H), 1.72-1.95 (m, 4H), 2.51-2.73 (m, 1H), 3.18 (s, 3H),3.47 (d, J = 6.3 Hz, 2H), 3.69 (s, 3H), 7.28-7.48 (m, 6H), 7.53-7.72 (m,4H). LC/MS: condition 1, retention time = 5.67 min LC/MS (ESI⁺) m/z; 440[M + H]⁺ 23 ¹H-NMR (CDCl₃) δ: 1.07 (s, 9H), 1.42-1.68 (m, 5H), 1.87-2.00(m, 3H), 2.01-2.13 (m, 1H), 3.53 (d, J = 6.0 Hz, 2H), 3.81-4.00 (m, 1H),7.20-7.27 (m, 1H), 7.30-7.43 (m, 6H), 7.45-7.53 (m, 1H), 7.59-7.73 (m,4H), 9.01 (d, J = 4.5 Hz, 1H), 9.07 (br s, 1H). LC/MS: condition 1,retention time = 5.94 min LC/MS (ESI⁺) m/z; 498 [M + H]⁺ 24 ¹H-NMR(CDCl₃) δ: 1.09 (s, 9H), 1.17-1.37 (m, 2H), 1.68-1.82 (m, 1H), 1.83-2.21(m, 6H), 3.07-3.22 (m, 1H), 3.58 (d, J = 6.3 Hz, 2H), 6.75-6.85 (m, 1H),7.25-7.32 (m, 1H), 7.33-7.50 (m, 6H), 7.62-7.78 (m, 4H), 9.01 (br s,1H), 9.21 (s, 1H). LC/MS: condition 1, retention time = 5.67 min LC/MS(ESI⁺) m/z; 510 [M + H]⁺ LC/MS (ESI⁻) m/z; 508 [M − H]⁻

TABLE^(a) 83 Rf Data 25 ¹H-NMR (CDCl₃) δ: 0.90-0.98 (m, 3H), 1.45 (s,9H), 1.30-1.90 (m, 4H), 2.05-2.30 (m, 1H), 2.50-2.85 (m, 1H), 3.30-3.50(m, 1H), 3.50-4.20 (m, 4H). 26 ¹H-NMR (CDCl₃) δ: 0.87-1.01 (m, 3H),1.41-1.47 (m, 9H), 1.54-1.79 (m, 4H), 2.80 (s, 2H), 2.89 (q, J = 6.3 Hz,1H), 3.15-3.22 (m, 3H), 3.56 (br s, 1H), 3.68-3.73 (m, 3H). LC/MS:condition 1, retention time = 3.97 min LC/MS (ESI⁺) m/z; 231 [M −^(t)Bu]⁺ 27 LC/MS: condition 1, retention time = 4.12 min LC/MS (ESI⁺)m/z; 345 [M + H]⁺ LC/MS (ESI⁻) m/z; 343 [M − H]⁻ 28 ¹H-NMR (CDCl₃) δ:1.46 (s, 9H), 1.48-1.56 (m, 1H), 1.58-1.76 (m, 2H), 1.88-1.97 (m, 1H),2.63-2.95 (m, 3H), 3.19 (s, 3H), 3.73 (s, 3H), 4.03-4.22 (m, 2H). LC/MS:condition 1, retention time = 3.60 min LC/MS (ESI⁺) m/z; 273 [M −^(t)Bu]⁺ 29 LC/MS: condition 1, retention time = 3.87 min LC/MS (ESI⁺)m/z; 275 [M − ^(t)Bu]⁺ LC/MS (ESI⁻) m/z; 329 [M − H]⁻ 30 LC/MS:condition 1, retention time = 2.88 min LC/MS (ESI⁺) m/z; 222 [M + H]⁺ 31LC/MS: condition 1, retention time = 3.52 min LC/MS (ESI⁺) m/z; 235 [M +H]⁺ LC/MS (ESI⁻) m/z; 233 [M − H]⁻ 32 ¹H-NMR (CDCl₃) δ: 1.65-1.75 (m,2H), 1.80-1.87 (m, 1H), 2.16-2.23 (m, 1H), 2.91-3.02 (m, 1H), 3.22 (brs, 1H), 4.08-4.19 (m, 2H), 4.38 (br s, 1H), 5.10-5.18 (m, 2H), 7.21 (dd,J = 3.6, 2.0 Hz, 1H), 7.28-7.39 (m, 5H), 7.51 (dd, J = 4.0, 2.3 Hz, 1H),8.95 (br s, 1H), 9.42 (br s, 1H). LC/MS: condition 1, retention time =3.90 min LC/MS (ESI⁺) m/z; 365 [M + H]⁺ LC/MS (ESI⁻) m/z; 363 [M − H]⁻33 ¹H-NMR (CDCl₃) δ: 1.35-1.80 (m, 3H), 2.00-2.15 (m, 1H), 2.40-2.59 (m,1H), 2.93 (ddd, J = 13.0, 10.7, 3.0 Hz, 1H), 2.95-3.26 (m, 1H),3.92-4.02 (m, 1H), 4.02-4.35 (m, 1H), 5.11 (d, J = 12.4 Hz, 1H), 5.16(d, J = 12.4 Hz, 1H), 7.27-7.34 (m, 5H). LC/MS: condition 1, retentiontime = 3.52 min LC/MS (ESI⁺) m/z; 264 [M + H]⁺ LC/MS (ESI⁻) m/z; 262 [M− H]⁻ 34 ¹H-NMR (CDCl₃) δ: 1.40-1.81 (m, 3H), 1.87-2.00 (m, 1H),2.68-3.05 (m, 3H), 3.16 (s, 3H), 3.59-3.70 (m, 3H), 4.05-4.34 (m, 2H),5.11 (d, J = 12.7 Hz, 1H), 5.16 (d, J = 12.7 Hz, 1H), 7.28-7.39 (m, 5H).LC/MS: condition 1, retention time = 3.70 min LC/MS (ESI⁺) m/z; 307 [M +H]⁺ 35 LC/MS: condition 1, retention time = 0.77 min LC/MS (ESI⁺) m/z;321 [M + H]⁺

TABLE^(a) 84 Rf Data 36 ¹H-NMR (CDCl₃) δ: 1.16-1.40 (m, 3H), 1.61-1.82(m, 1H), 1.85-2.09 (m, 4H), 2.10-2.26 (m, 2H), 3.09-3.25 (m, 1H), 3.58(t, J = 6.0 Hz, 2H), 6.74-6.85 (m, 1H), 7.20-7.32 (m, 1H), 9.04 (br s,1H), 9.22 (s, 1H). LC/MS: condition 1, retention time = 2.99 min LC/MS(ESI⁺) m/z; 272 [M + H]⁺ LC/MS (ESI⁻) m/z; 270 [M − H]⁻ 37 ¹H-NMR(CDCl₃) δ: 0.93-1.13 (m, 2H), 1.20-1.32 (m, 1H), 1.44-1.65 (m, 2H),1.78-1.93 (m, 4H), 2.56-2.74 (m, 1H), 3.18 (s, 3H), 3.48 (t, J = 6.0 Hz,2H), 3.69 (s, 3H). LC/MS: condition 1, retention time = 1.22 min LC/MS(ESI⁺) m/z; 202 [M + H]⁺ 38 ¹H-NMR (CDCl₃) δ: 1.46 (s, 9H), 1.60-1.81(m, 4H), 2.65-2.90 (m, 3H), 3.18 (s, 3H), 3.71 (s, 3H), 4.00-4.30 (m,2H). LC/MS: condition 1, retention time = 3.66 min LC/MS (ESI⁺) m/z; 273[M + H]⁺ 39 ¹H-NMR (CDCl₃) δ: 1.40-1.53 (m, 9H), 1.55-1.82 (m, 2H),1.87-2.10 (m, 2H), 2.80-3.10 (m, 2H), 4.00-4.37 (m, 3H), 7.15-7.30 (m,1H), 7.46-7.59 (m, 1H), 8.90-9.08 (m, 1H), 9.53 (br s, 1H). LC/MS:condition 1, retention time = 3.87 min LC/MS (ESI⁺) m/z; 331 [M + H]⁺LC/MS (ESI⁻) m/z; 329 [M − H]⁻ 40 ¹H-NMR (DMSO-d₆) δ: 1.63-1.89 (m, 4H),2.82-3.04 (m, 3H), 3.10 (s, 3H), 3.18-3.31 (m, 2H), 3.69 (s, 3H), 8.73(br s, 1H), 9.07 (br s, 1H). LC/MS: condition 1, retention time = 0.50min LC/MS (ESI⁺) m/z; 173 [M + H]⁺ 41 ¹H-NMR (CDCl₃) δ: 1.65-1.92 (m,4H), 2.38-2.51 (m, 2H), 2.57-2.72 (m, 1H), 2.92-3.06 (m, 4H), 3.18 (s,3H), 3.70 (s, 3H). LC/MS: condition 1, retention time = 0.74 min LC/MS(ESI⁺) m/z; 255 [M + H]⁺ 42 ¹H-NMR (CDCl₃) δ: 1.78-2.05 (m, 4H),2.56-2.68 (m, 2H), 2.87-3.12 (m, 4H), 3.87-4.00 (m, 1H), 7.22-7.25 (m,1H), 7.26 (s, 1H), 7.50-7.56 (m, 1H), 8.99 (s, 1H), 9.74 (br s, 1H).LC/MS: condition 1, retention time = 2.75 min LC/MS (ESI⁺) m/z; 313 [M +H]⁺ 43 ¹H-NMR (CDCl₃) δ: 1.64-1.82 (m, 4H), 2.76-2.95 (m, 3H), 3.18 (s,3H), 3.71 (s, 3H), 4.12-4.30 (m, 2H), 5.13 (s, 2H), 7.25-7.39 (m, 5H).LC/MS: condition 1, retention time = 3.65 min LC/MS (ESI⁺) m/z; 307 [M +H]⁺ 44 ¹H-NMR (CDCl₃) δ: 1.60-1.82 (m, 3H), 1.92-2.09 (m, 2H), 2.95-3.15(m, 2H), 4.18-4.38 (m, 2H), 5.15 (s, 2H), 7.20-7.25 (m, 1H), 7.25-7.40(m, 5H), 7.50-7.55 (m, 1H), 8.99 (s, 1H), 9.44-9.71 (m, 1H). LC/MS:condition 1, retention time = 3.90 min LC/MS (ESI⁺) m/z; 365 [M + H]⁺

TABLE^(a) 85 Rf Data 45 ¹H-NMR (CDCl₃) δ: 1.02-1.25 (m, 2H), 1.44 (s,9H), 1.52-1.71 (m, 2H), 1.78-1.89 (m, 2H), 2.02-2.15 (m, 2H), 2.52-2.68(m, 1H), 3.17 (s, 3H), 3.35-3.50 (m, 1H), 3.69 (s, 3H), 4.28-4.43 (m,1H). 46 ¹H-NMR (CDCl₃) δ: 1.26-1.41 (m, 2H), 1.46 (s, 9H), 1.52-1.80 (m,3H), 2.00-2.20 (m, 3H), 3.49 (br s, 1H), 3.82-3.99 (m, 1H), 4.46 (br s,1H), 7.19-7.25 (m, 1H), 7.46-7.55 (m, 1H), 9.00 (s, 1H), 9.44-9.85 (m,1H). LC/MS: condition 1, retention time = 3.84 min LC/MS (ESI⁺) m/z; 345[M + H]⁺ LC/MS (ESI⁻) m/z; 343 [M − H]⁻ 47 LC/MS: condition 1, retentiontime = 2.01 min LC/MS (ESI⁺) m/z; 321 [M + H]⁺ 48 LC/MS: condition 1,retention time = 2.18 min LC/MS (ESI⁺) m/z; 379 [M + H]⁺ LC/MS (ESI⁻)m/z; 377 [M − H]⁻ 49 ¹H-NMR (CDCl₃) δ: 0.94-1.13 (m, 2H), 1.42-1.71 (m,4H), 1.75-1.93 (m, 4H), 2.55-2.73 (m, 1H), 3.10-3.26 (m, 4H), 3.32 (s,3H), 3.68 (s, 3H). LC/MS: condition 1, retention time = 3.19 min LC/MS(ESI⁺) m/z; 216 [M + H]⁺ 50 ¹H-NMR (CDCl₃) δ: 1.10-1.30 (m, 2H),1.41-1.78 (m, 3H), 1.86-2.12 (m, 4H), 3.25 (d, J = 6.3 Hz, 2H), 3.35 (s,3H), 3.85-4.02 (m, 1H), 7.15-7.30 (m, 1H), 7.45-7.55 (m, 1H), 9.00 (s,1H), 9.46 (br s, 1H). LC/MS: condition 1, retention time = 3.65 minLC/MS (ESI⁺) m/z; 274 [M + H]⁺ LC/MS (ESI⁻) m/z; 272 [M − H]⁻ 51 ¹H-NMR(CDCl₃) δ: 1.20-1.41 (m, 1H), 1.48-1.70 (m, 4H), 1.77-1.92 (m, 2H),2.00-2.13 (m, 1H), 2.50-2.73 (m, 1H), 3.18 (s, 3H), 3.55-3.78 (m, 1H),3.70 (s, 3H). LC/MS: condition 1, retention time = 0.60 min LC/MS (ESI⁺)m/z; 189 [M + H]⁺ 52 ¹H-NMR (CDCl₃) δ: 1.22 (qd, J = 13.8, 2.7 Hz, 2H),1.55 (qd, J = 13.8, 2.7 Hz, 2H), 1.86 (m, 2H), 2.15 (m, 2H), 2.64 (m,1H), 3.14 (m, 1H), 3.17 (s, 3H), 3.36 (s, 3H), 3.70 (s, 3H). LC/MS:condition 1, retention time = 1.77 min LC/MS (ESI⁺) m/z; 202 [M + H]⁺ 53¹H-NMR (CDCl₃) δ: 1.50 (m, 4H), 2.15 (m, 4H), 3.21 (tt, J = 10.5, 3.9Hz, 1H), 3.40 (s, 3H), 3.95 (tt, J = 11.4, 3.6 Hz, 1H), 7.23 (dd, J =3.3, 2.1 Hz, 1H), 7.56 (t, J = 2.4 Hz, 1H), 9.03 (s, 1H), 10.9 (br s,1H). LC/MS: condition 1, retention time = 3.35 min LC/MS (ESI⁺) m/z; 260[M + H]⁺ LC/MS (ESI⁻) m/z; 258 [M − H]⁻

TABLE^(a) 86 Rf Data 54 ¹H-NMR (CDCl₃) δ: 1.60-1.95 (m, 6H), 2.10-2.30(m, 2H), 2.64-2.83 (m, 1H), 3.18 (s, 3H), 3.71 (s, 3H). LC/MS: condition1, retention time = 3.05 min LC/MS (ESI⁺) m/z; 208 [M + H]⁺ 55 LC/MS:condition 1, retention time = 3.60 min LC/MS (ESI⁺) m/z; 184 [M + H]⁺ 56¹H-NMR (CDCl₃) δ: 1.35-1.88 (m, 12H), 2.73-2.90 (m, 1H), 3.17 (s, 3H),3.69 (s, 3H). LC/MS: condition 1, retention time = 3.81 min LC/MS (ESI⁺)m/z; 186 [M + H]⁺ 57 ¹H-NMR (CDCl₃) δ: 1.96 (m, 2H), 2.13 (m, 2H), 2.33(m, 2H), 3.17 (s, 3H), 3.48 (m, 1H), 3.65 (s, 3H). LC/MS: condition 1,retention time = 1.85 min LC/MS (ESI⁺) m/z; 144 [M + H]⁺ 58 ¹H-NMR(CDCl₃) δ: 1.57 (m, 2H), 1.78 (m, 6H), 3.10 (m, 1H), 3.19 (s, 3H), 3.69(s, 3H). LC/MS: condition 1, retention time = 2.94 min LC/MS (ESI⁺) m/z;158 [M + H]⁺ 59 ¹H-NMR (CDCl₃) δ: 1.28-1.64 (m, 4H), 1.83-2.19 (m, 5H),2.57-2.76 (m, 1H), 3.18 (s, 3H), 3.70 (s, 3H). LC/MS: condition 1,retention time = 3.74 min LC/MS (ESI⁺) m/z; 240 [M + H]⁺ 60 ¹H-NMR(CDCl₃) δ: 1.45-1.80 (m, 4H), 1.82-2.20 (m, 5H), 2.81-2.99 (m, 1H), 3.17(s, 3H), 3.68 (s, 3H). LC/MS: condition 1, retention time = 3.77 minLC/MS (ESI⁺) m/z; 240 [M + H]⁺ 61 ¹H-NMR (CDCl₃) δ: 1.75-2.35 (m, 8H),3.94-4.13 (m, 1H), 7.20-7.30 (m, 1H), 7.46-7.58 (m, 1H), 8.99 (s, 1H),9.13 (br s, 1H). LC/MS: condition 1, retention time = 3.69 min LC/MS(ESI⁺) m/z; 266 [M + H]⁺ LC/MS (ESI⁻) m/z; 264 [M − H]⁻ 62 ¹H-NMR(CDCl₃) δ: 1.16-1.74 (m, 7H), 1.96 (ddd, J = 12.9, 5.1, 3.3 Hz, 1H),2.36 (br s, 1H), 2.86 (br s, 1H), 4.31 (m, 1H), 7.24 (m, 1H), 7.51 (m,1H), 9.01 (s, 1H), 9.75 (br s, 1H). LC/MS: condition 1, retention time =3.92 min LC/MS (ESI⁺) m/z; 242 [M + H]⁺ LC/MS (ESI⁻) m/z; 240 [M − H]⁻63 ¹H-NMR (CDCl₃) δ: 1.60-1.82 (m, 10H), 2.03 (m, 2H), 4.16 (tt, J =8.7, 4.5 Hz, 1H), 7.24 (m, 1H), 7.57 (m, 1H), 9.03 (s, 1H), 11.18 (br s,1H). LC/MS: condition 1, retention time = 4.11 min LC/MS (ESI⁺) m/z; 244[M + H]⁺ LC/MS (ESI⁻) m/z; 242 [M − H]⁻

TABLE^(a) 87 Rf Data 64 ¹H-NMR (CDCl₃) δ: 1.95 (m, 1H), 2.14 (m, 1H),2.38 (m, 4H), 4.60 (quint, J = 8.4 Hz, 1H), 7.28 (m, 1H), 7.52 (m, 1H),8.97 (s, 1H). LC/MS: condition 1, retention time = 3.22 min LC/MS (ESI⁺)m/z; 202 [M + H]⁺ LC/MS (ESI⁻) m/z; 200 [M − H]⁻ 65 ¹H-NMR (CDCl₃) δ:1.76 (m, 4H), 1.91 (m, 2H), 2.03 (m, 2H), 4.36 (m, 1H), 7.26 (m, 1H),7.55 (m, 1H), 9.03 (s, 1H), 10.43 (br s, 1H). LC/MS: condition 1,retention time = 3.64 min LC/MS (ESI⁺) m/z; 216 [M + H]⁺ 66 ¹H-NMR(DMSO-d₆) δ: 1.30-1.60 (m, 4H), 1.90-2.13 (m, 4H), 2.20-2.45 (m, 1H),3.80-4.00 (m, 1H), 6.91-7.05 (m, 1H), 7.75-7.90 (m, 1H), 8.96 (s, 1H),12.47 (br s, 1H). LC/MS: condition 1, retention time = 4.07 min LC/MS(ESI⁺) m/z; 298 [M + H]⁺ LC/MS (ESI⁻) m/z; 296 [M − H]⁻ 67 ¹H-NMR(DMSO-d₆) δ: 1.50-1.88 (m, 6H), 1.95-2.11 (m, 2H), 2.30-2.45 (m, 1H),4.05-4.20 (m, 1H), 6.90-7.05 (m, 1H), 7.75-7.90 (m, 1H), 8.93 (s, 1H),12.46 (br s, 1H). LC/MS: condition 1, retention time = 4.00 min LC/MS(ESI⁺) m/z; 298 [M + H]⁺ LC/MS (ESI⁻) m/z; 296 [M − H]⁻ 68 ¹H-NMR(CDCl₃) δ: 1.05 (s, 9H), 1.38 (dq, J = 10.9, 3.0 Hz, 4H), 1.65-1.74 (m,2H), 1.86-1.95 (m, 2H), 2.53-2.65 (m, 1H), 3.13 (s, 3H), 3.56-3.64 (m,1H), 3.67 (s, 3H), 7.32-7.45 (m, 6H), 7.64-7.69 (m, 4H). LC/MS:condition 1, retention time = 5.45 min LC/MS (ESI⁺) m/z; 426 [M + H]⁺ 69¹H-NMR (CDCl₃) δ: 1.07 (s, 9H), 1.30-1.45 (m, 2H), 1.52-1.67 (m, 2H),1.89-2.00 (m, 4H), 3.60-3.71 (m, 1H), 3.89 (tt, J = 12.2, 3.0 Hz, 1H),7.17 (dd, J = 3.6, 2.0 Hz, 1H), 7.33-7.49 (m, 7H), 7.65-7.72 (m, 4H),8.99 (s, 1H), 9.11 (br s, 1H). LC/MS: condition 1, retention time = 5.64min LC/MS (ESI⁺) m/z; 484 [M + H]⁺ LC/MS (ESI⁻) m/z; 482 [M − H]⁻ 70¹H-NMR (CDCl₃) δ: 1.09 (s, 5H), 1.15 (s, 4H), 1.53-1.97 (m, 5H),1.98-2.08 (m, 2H), 2.49 (dq, J = 12.6, 3.0 Hz, 1H), 3.11 (tt, J = 11.2,3.3 Hz, 0.6H), 3.25 (tt, J = 12.2, 3.3 Hz, 0.4H), 3.75-3.85 (m, 0.6H),4.13-4.18 (m, 0.4H), 6.71 (dd, J = 3.3, 2.0 Hz, 0.6H), 7.01 (dd, J =3.0, 2.3 Hz, 0.4H), 7.16 (t, J = 3.3 Hz, 0.6H), 7.21-7.28 (m, 0.4H),7.34-7.47 (m, 6H), 7.69-7.75 (m, 4H), 9.04 (br s, 1H), 9.18 (s, 0.6H),9.24 (s, 0.4H). LC/MS: condition 1, retention time = 5.32, 5.39 min(cis/trans mixture) LC/MS (ESI⁺) m/z; 496 [M + H]⁺ LC/MS (ESI⁻) m/z; 494[M − H]⁻

TABLE^(a) 88 Rf Data 71 ¹H-NMR (CDCl₃) δ: 1.31-1.46 (m, 1H), 1.54-1.67(m, 4H), 1.81-1.99 (m, 3H), 2.02-2.10 (m, 1H), 2.57-2.79 (m, 1H), 3.18(d, J = 1.3 Hz, 3H), 3.70 (d, J = 1.7 Hz, 3H), 3.98-4.04 (m, 1H). LC/MS:condition 1, retention time = 0.86 min (cis/trans mixture) LC/MS (ESI⁺)m/z; 188 [M + H]⁺ 72 ¹H-NMR (CDCl₃) δ: 0.03-0.05 (m, 6H), 0.85 (s, 4H),0.86 (s, 5H), 1.27-1.52 (m, 4H), 1.67-1.82 (m, 2H), 1.93 (td, J = 11.9,3.3 Hz, 2H), 2.53-2.66 (m, 1H), 3.14 (s, 3H), 3.66 (s, 3H), 3.94-3.98(m, 1H). LC/MS: condition 1, retention time = 4.83, 5.00 min (cis/transmixture) LC/MS (ESI⁺) m/z; 302 [M + H]⁺ 73 ¹H-NMR (CDCl₃) δ: 0.05 (s,4H), 0.08 (s, 2H), 0.90 (s, 9H), 1.49-1.83 (m, 6H), 1.93-2.08 (m, 2H),3.59-3.69 (m, 0.3H), 3.93 (tt, J = 11.2, 3.0 Hz, 1H), 4.02-4.07 (m,0.7H), 7.20-7.26 (m, 1H), 7.52 (dd, J = 4.3, 2.3 Hz, 1H), 9.01 (s,0.7H), 9.02 (s, 0.3H), 9.78 (br s, 1H). LC/MS: condition 1, retentiontime = 5.07, 5.14 min (cis/trans mixture) LC/MS (ESI⁺) m/z; 360 [M + H]⁺LC/MS (ESI⁻) m/z; 358 [M − H]⁻ 74 ¹H-NMR (CDCl₃) δ: 0.11 (s, 3H), 0.14(s, 3H), 0.93 (s, 4.5H), 0.98 (s, 4.5H), 1.50-1.81 (m, 3H), 1.83-2.17(m, 4H), 2.37 (dq, J = 12.9, 4.0 Hz, 1H), 3.15 (tt, J = 11.9, 4.0 Hz,0.5H), 3.29 (tt, J = 12.6, 4.0 Hz, 0.5H), 3.72-3.84 (m, 0.5H), 4.17 (brs, 0.5H), 6.77 (dd, J = 3.6, 2.0 Hz, 0.5H), 7.12 (dd, J = 3.6, 2.0 Hz,0.5H), 7.24-7.27 (m, 0.5H), 7.30 (t, J = 3.3 Hz, 0.5H), 9.13 (br s, 1H),9.22 (s, 0.5H), 9.23 (s, 0.5H). LC/MS: condition 1, retention time =4.88, 4.97 min (cis/trans mixture) LC/MS (ESI⁺) m/z; 372 [M + H]⁺ LC/MS(ESI⁻) m/z; 370 [M − H]⁻ 75 ¹H-NMR (DMSO-d₆) δ: 1.35-1.51 (m, 1H),1.59-1.71 (m, 1H), 1.71-1.86 (m, 2H), 1.92-2.03 (m, 3H), 3.10 (dt, J =12.9, 3.6 Hz, 0.7H), 3.18 (dt, J = 15.2, 3.0 Hz, 0.3H), 3.51-3.63 (m,0.7H), 3.92-3.99 (m, 0.3H), 4.51 (d, J = 2.6 Hz, 0.3H), 4.61 (d, J = 4.3Hz, 0.7H), 6.82 (dd, J = 3.3, 1.7 Hz, 0.7H), 6.97 (dd, J = 3.3, 1.7 Hz,0.3H), 7.48 (t, J = 3.0 Hz, 1H), 9.51 (s, 0.7H), 9.51 (s, 0.3H), 12.51(br s, 1H). 76 ¹H-NMR (CDCl₃) δ: −0.04 (s, 9H), 0.94 (t, J = 8.1 Hz,2H), 1.73 (qd, J = 12.4, 3.8 Hz, 2H), 2.00 (br s, 2H), 3.01 (t, J = 12.2Hz, 2H), 3.55 (t, J = 8.0 Hz, 2H), 4.16 (tt, J = 11.4, 3.6 Hz, 2H), 4.29(br s, 2H), 5.12 (s, 2H), 5.71 (s, 2H), 7.26 (d, J = 3.6Hz, 1H),7.31-7.40 (m, 5H), 7.57 (d, J = 3.6Hz, 1H), 9.03 (s, 1H). LC/MS:condition 3, retention time = 3.29 min LC/MS (ESI⁺) m/z; 495 [M + H]⁺

TABLE^(a) 89 Rf Data 77 ¹H-NMR (CDCl₃) δ: −0.07 (s, 9H), 0.91 (t, J =8.3 Hz, 2H), 1.27-1.38 (m, 3H), 1.97-2.02 (m, 2H), 2.70-2.74 (m, 2H),3.53 (t, J = 8.3 Hz, 2H), 4.02-4.23 (m, 3H), 5.10 (s, 2H), 5.64 (d, J =2.4Hz, 2H), 6.61 (d, J = 3.3Hz, 1H), 7.26-7.33 (m, 6H), 8.85 (s, 1H).LC/MS: condition 3, retention time = 2.26 min LC/MS (ESI⁺) m/z; 496 [M +H]⁺ 78 LC/MS: condition 3, retention time = 3.05 min LC/MS (ESI⁺) m/z;506 [M + H]⁺ 79 LC/MS: condition 3, retention time = 1.55 min LC/MS(ESI⁺) m/z; 366 [M + H]⁺ 80 LC/MS: condition 3, retention time = 0.70min LC/MS (ESI⁺) m/z; 231 [M + H]⁺ 81 LC/MS: condition 3, retention time= 1.63 min LC/MS (ESI⁺) m/z; 389 [M + H]⁺ LC/MS (ESI⁻) m/z; 387 [M − H]⁻82 LC/MS: condition 3, retention time = 1.08 min LC/MS (ESI⁺) m/z; 390[M + H]⁺ 83 ¹H-NMR (CDCl₃) δ: 3.20 (s, 3H), 3.65 (s, 3H), 3.68-3.70 (m,1H), 4.14 (t, J = 8.7 Hz, 2H), 4.22 (d, J = 6.0 Hz, 2H), 5.09 (s, 2H),7.30-7.36 (m, 5H). LC/MS: condition 3, retention time = 1.88 min LC/MS(ESI⁺) m/z; 279 [M + H]⁺ 84 ¹H-NMR (CDCl₃) δ: 4.31-4.41 (m, 4H),4.62-4.69 (m, 2H), 5.11 (s, 2H), 7.27-7.36 (m, 6H), 7.55 (dd, J = 3.6,2.4 Hz, 1H), 8.95 (s, 1H), 9.18 (br s, 1H). LC/MS: condition 3,retention time = 2.09 min LC/MS (ESI⁺) m/z; 337 [M + H]⁺ 85 ¹H-NMR(CDCl₃) δ: 1.88 (br s, 1H). 3.35 (s, 3H), 3.55 (s, 3H), 4.74 (s, 2H),7.39 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H). LC/MS: condition 1,retention time = 0.84 min LC/MS (ESI⁺) m/z; 196 [M + H]⁺ 86 ¹H-NMR(CDCl₃) δ: 0.11 (s, 6H), 0.95 (s, 9H), 3.35 (s, 3H), 3.55 (s, 3H), 4.77(s, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 8.1 Hz, 2H). LC/MS:condition 1, retention time = 4.73 min LC/MS (ESI⁺) m/z; 310 [M + H]⁺ 87¹H-NMR (CDCl₃) δ: 0.12 (s, 6H), 0.96 (s, 9H), 4.83 (s, 2H), 7.00 (dd, J= 3.9, 2.1 Hz, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.49 (m, 1H), 8.14 (d, J =8.1 Hz, 2H), 9.04 (s, 1H), 9.59 (br s, 1H). LC/MS: condition 1,retention time = 4.80 min LC/MS (ESI⁺) m/z; 368 [M + H]⁺ LC/MS (ESI⁻)m/z; 366 [M − H]⁻ 88 ¹H-NMR (CDCl₃) δ: 0.15 (s, 6H), 0.98 (s, 9H), 4.84(s, 2H), 6.97 (dd, J = 3.3, 2.1 Hz, 1H), 7.27 (dd, J = 6.0, 3.3 Hz, 1H),7.50 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.4 Hz, 2H), 9.22 (br s, 1H),9.30 (s, 1H). LC/MS: condition 1, retention time = 4.93 min LC/MS (ESI⁺)m/z; 380 [M + H]⁺

TABLE^(a) 90 Rf Data 89 ¹H-NMR (CDCl₃) δ: 1.58 (m, 4H), 1.73 (m, 5H),2.80 (tt, J = 8.4, 3.6 Hz, 1H), 3.17 (s, 3H), 3.62 (m, 2H), 3.69 (s,3H). LC/MS: condition 1, retention time = 1.42 min LC/MS (ESI⁺) m/z; 202[M + H]⁺ 90 ¹H-NMR (CDCl₃) δ: 0.04 (s, 6H), 0.89 (s, 9H), 1.55 (m, 4H),1.69 (m, 5H), 2.80 (tt, J = 7.8, 4.2 Hz, 1H), 3.17 (s, 3H), 3.58 (d, J =10.5 Hz, 2H), 3.68 (s, 3H). LC/MS: condition 1, retention time = 5.08min LC/MS (ESI⁺) m/z; 316 [M + H]⁺ 91 ¹H-NMR (CDCl₃) δ: 0.06 (s, 6H),0.90 (s, 9H), 1.71 (m, 7H), 1.90 (m, 2H), 3.53 (d, J = 6.9 Hz, 2H), 4.07(m, 1H), 7.20 (dd, J = 3.3 2.1 Hz, 1H), 7.50 (t, J = 3.3 Hz, 1H), 8.98(s, 1H), 9.42 (br s, 1H). LC/MS: condition 1, retention time = 5.19 minLC/MS (ESI⁺) m/z; 374 [M + H]⁺ LC/MS (ESI⁻) m/z; 372 [M − H]⁻ 92 ¹H-NMR(CDCl₃) δ: 0.08 (s, 6H), 0.93 (s, 9H), 1.22 (m, 2H), 1.70 (m, 1H),1.90-2.05 (m, 4H), 2.15 (m, 2H), 3.16 (m, 1H), 3.51 (d, J = 6.6 Hz, 2H),6.08 Hz (m, 1H), 7.27 (m, 1H), 9.16 (br s, 1H), 9.22 (s, 1H). LC/MS:condition 1, retention time = 5.09 min LC/MS (ESI⁺) m/z; 428 [M + H]⁺LC/MS (ESI⁻) nn/z; 426 [M − H]⁻ 93 LC/MS: condition 1, retention time =3.62 min LC/MS (ESI⁺) m/z; 202, 204 [M + H]⁺ 94 ¹H-NMR (CDCl₃) δ:1.83-2.04 (m, 4H), 2.25 (td, J = 11.6, 2.5 Hz, 2H), 2.93 (d, J = 11.7Hz, 2H), 3.59 (s, 2H), 3.92-3.99 (m, 1H), 7.24 (dd, J = 3.6, 2.1 Hz,1H), 7.47 (d, J = 8.1 Hz, 2H), 7.50 (dd, J = 3.6, 2.4 Hz, 1H), 7.61 (d,J = 8.1 Hz, 2H), 8.98 (s, 1H), 9.04 (br s, 1H). LC/MS: condition 3,retention time = 1.25 min LC/MS (ESI⁺) m/z; 346 [M + H]⁺ 95 ¹H-NMR(CDCl₃) δ: −0.06 (s, 9H), 0.91 (t, J = 8.3 Hz, 2H), 1.78-2.04 (m, 4H),2.25 (td, J = 11.6, 2.8 Hz, 2H), 2.93 (d, J = 11.7 Hz, 2H), 3.53 (t, J =8.3 Hz, 2H), 3.60 (s, 2H), 3.95 (tt, J = 11.4, 3.9 Hz, 1H), 5.68 (s,2H), 7.23 (d, J = 3.3 Hz, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.53 (d, J =3.6 Hz, 1H), 7.61 (d, J = 8.7 Hz, 2H), 8.99 (s, 1H). LC/MS: condition 3,retention time = 2.19 min LC/MS (ESI⁺) m/z; 476 [M + H]⁺ 96 ¹H-NMR(CDCl₃) δ: −0.07 (s, 9H), 0.90 (t, J = 8.1 Hz, 2H), 1.23 (d, J = 14.4Hz, 1H), 1.31-1.53 (m, 2H), 1.78-2.01 (m, 6H), 2.73 (d, J = 10.5 Hz,1H), 2.89 (d, J = 11.4 Hz, 1H), 3.49 (s, 2H), 3.54 (t, J = 8.1 Hz, 2H),4.05 (d, J = 7.5 Hz, 1H), 5.65 (d, J = 2.1 Hz, 2H), 6.63 (d, J = 3.6 Hz,1H), 7.32 (d, J = 3.6 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.57 (d, J =8.1 Hz, 2H), 8.86 (s, 1H). LC/MS: condition 3, retention time = 1.64 minLC/MS (ESI⁺) m/z; 477 [M + H]⁺ 97 LC/MS: condition 3, retention time =2.15 min LC/MS (ESI⁺) m/z; 487 [M + H]⁺

TABLE^(a) 91 Rf Data 98 ¹H-NMR (CDCl₃) δ: 2.05-2.20 (m, 2H), 3.20 (s,3H), 3.39-3.80 (m, 8H), 5.14 (s, 2H), 7.28-7.39 (m, 5H). LC/MS:condition 3, retention time = 2.02 min LC/MS (ESI⁺) rn/z; 293 [M + H]⁺99 LC/MS: condition 3, retention time = 2.13 min LC/MS (ESI⁺) m/z; 351[M + H]⁺ LC/MS (ESI⁻) m/z; 349 [M − H]⁻ 100 ¹H-NMR (CDCl₃) δ: 2.74 (brs, 2H), 2.96 (d, J = 12.0 Hz, 1H), 3.54 (d, J = 12.0 Hz, 1H), 7.35 (d, J= 9.0 Hz, 2H), 7.50 (d, J = 9.0 Hz, 2H). LC/MS: condition 1, retentiontime = 0.78 min LC/MS (ESI⁺) m/z; 240, 242 [M + H]⁺ 101 ¹H-NMR (CDCl₃)δ: 2.69 (br s, 1H), 3.02 (d, J = 13.2 Hz, 1H), 3.52 (d, J = 13.2 Hz,1H), 7.38 (m, 3H), 7.57 (m, 2H). LC/MS: condition 1, retention time =0.55 min LC/MS (ESI⁺) m/z; 206 [M + H]⁺ 102 ¹H-NMR (CDCl₃) δ: 2.97 (d, J= 12.9 Hz, 1H), 3.57 (d, J = 13.2 Hz, 1H), 7.08 (m, 2H), 7.55 (m, 2H).LC/MS: condition 1, retention time = 0.56 min LC/MS (ESI⁺) m/z; 224 [M +H]⁺ 103 ¹H-NMR (CDCl₃) δ: 2.77 (ddd, J = 5.5, 2.5, 1.2 Hz, 1H), 3.19(ddd, J = 5.5, 4.0, 1.1 Hz, 1H), 3.92 (dd, J = 4.0, 2.5 Hz, 1H), 7.40(d, J = 8.3 Hz, 2H), 7.61 (d, J = 8.3 Hz, 2H). 104 ¹H-NMR (CD₃OD) δ:1.91 (s, 3H), 2.20-2.33 (m, 4H), 3.20-3.30 (m, 2H), 3.50-3.69 (m, 3H),6.95 (d, J = 3.3 Hz, 1H), 7.43 (d, J = 3.3 Hz, 1H), 9.34 (s, 1H). LC/MS:condition 1, retention time = 2.15 min LC/MS (ESI⁺) m/z; 243 [M + H]⁺LC/MS (ESI⁻) m/z; 241 [M − H]⁻

TABLE^(a) 92 Rf Data 105 ¹H-NMR (CDCl₃) δ: 4.87 (s, 2H), 7.11 (d, J =8.9 Hz, 2H), 7.92 (d, J = 8.9 Hz, 2H), 9.95 (s, 1H). 106 ¹H-NMR(DMSO-d₆) δ: 4.72 (s, 2H), 7.38 (br s, 1H), 7.50 (d, J = 8.1 Hz, 2H),7.83 (d, J = 8.1 Hz, 2H), 7.97 (br s, 1H). LC/MS: condition 3, retentiontime = 1.48 min LC/MS (ESI⁺) m/z; 213, 215 [M + H]⁺ 107 ¹H-NMR (CDCl₃)δ: 4.49 (s, 2H), 7.73-7.81 (m, 2H), 7.87 (s, 1H). 108 ¹H-NMR (CDCl₃) δ:4.48 (s, 2H), 7.74-7.84 (m, 3H). 109 ¹H-NMR (CDCl₃) δ: 4.50 (s, 2H),7.70 (d, J = 8.7 Hz, 1H), 7.81-7.84 (m, 2H). 110 ¹H-NMR (CDCl₃) δ: 1.43(s, 9H), 2.87 (t, J = 6.9 Hz, 2H), 3.39 (q, J = 6.9 Hz, 2H), 4.54 (br s,1H), 7.31 (d, J = 8.6 Hz, 2H), 7.58-7.62 (m, 2H). 111 ¹H-NMR (CDCl₃) δ:2.83 (q, J = 6.9 Hz, 2H), 2.97-3.04 (m, 2H), 7.27-7.37 (m, 2H),7.58-7.65 (m, 2H). 112 ¹H-NMR (CDCl₃) δ: 1.48 (s, 9H), 4.70 (s, 4H). 113¹H-NMR (CDCl₃) δ: 1.44 (s, 9H), 1.52 (s, 3H), 1.99 (s, 1H), 3.82 (d, J =8.9 Hz, 2H), 3.86 (d, J = 8.9 Hz, 2H). 115 ¹H-NMR (CDCl₃) δ: 4.06 (d, J= 12.5 Hz, 2H), 4.23 (d, J = 12.5 Hz, 2H), 7.96 (s, 1H), 9.76 (br s,2H). 116 ¹H-NMR (CDCl₃) δ: 1.44 (s, 9H), 3.77 (d, J = 8.6 Hz, 1H), 3.85(d, J = 8.6 Hz, 1H) 3.85-3.92 (m, 2H), 4.06-4.15 (m, 2H), 4.30-4.40 (m,1H). 118 ¹H-NMR (CDCl₃) δ: 3.01 (d, J = 13.2 Hz, 1H), 3.62 (d, J = 13.2Hz, 1H), 7.35 (m, 1H), 7.93 (m, 1H), 8.60 (m, 1H), 8.78 (s, 1H). LC/MS:condition 3, retention time = 0.39 min LC/MS (ESI⁺) m/z; 207 [M + H]⁺119 ¹H-NMR (CDCl₃) δ: 2.49 (s, 3H), 2.98 (d, J = 13.2 Hz, 1H), 3.52 (d,J = 13.2 Hz, 1H), 7.25 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H).LC/MS: condition 3, retention time = 1.44 min LC/MS (ESI⁺) m/z; 252 [M +H]⁺ 120 ¹H-NMR (CDCl₃) δ: 2.98 (d, J = 13.2 Hz, 1H), 3.55 (d, J = 13.2Hz, 1H), 3.94 (s, 3H) 6.76 (d, J = 8.7 Hz, 1H), 7.77 (dd, J = 8.1, 2.4Hz, 1H, 8.31 (d, J = 2.4 Hz, 1H). LC/MS: condition 3, retention time =0.54 min LC/MS (ESI⁺) m/z; 237 [M + H]⁺ 121 ¹H-NMR (CDCl₃) δ: 3.02 (d, J= 13.5 Hz, 1H), 3.37 (d, J = 13.5 Hz, 1H), 3.77 (s, 3H), 6.88 (d, J =9.0 Hz, 2H), 7.45 (d, J = 9.0 Hz, 2H).

TABLE^(a) 93 Rf Data 122 ¹H-NMR (CDCl₃) δ: 3.02 (d, J = 12.9 Hz, 1H),3.50 (d, J = 13.5 Hz, 1H), 3.88 (s, 3H), 3.91 (s, 3H), 6.86 (d, J = 8.7Hz, 1H), 7.04 (m, 1H), 7.17 (d, J = 1.8 Hz, 1H). 123 ¹H-NMR (CDCl₃) δ:1.34 (t, J = 7.2 Hz, 3H), 4.26 (q, J = 7.2 Hz, 2H), 6.35 (d, J = 15.9Hz, 1H), 7.07 (m, 2H), 7.51 (m, 2H), 7.64 (d, J = 15.9 Hz, 1H). LC/MS:condition 1, retention time = 4.17 min LC/MS (ESI⁺) m/z; 195 [M + H]⁺124 ¹H-NMR (CDCl₃) δ: 1.28 (m, 4H), 1.57 (m, 1H), 1.84 (m, 1H), 2.50 (m,1H), 4.17 (q, J = 7.2 Hz, 2H), 6.96 (m, 2H), 7.07 (m, 2H). 125 LC/MS:condition 1, retention time = 4.42 min LC/MS (ESI⁺) m/z; 296 [M + H]⁺126 ¹H-NMR (CDCl₃) δ: 0.85 (m, 2H), 1.22 (m, 1H), 1.71 (m, 3H), 2.72 (m,2H), 6.89-7.05 (m, 4H). 127 LC/MS: condition 1, retention time = 0.33min LC/MS (ESI⁺) m/z; 168 [M + H]⁺ 128a ¹H-NMR (CDCl₃) δ: 1.52-1.80 (m,9H), 2.05-2.25 (m, 3H), 3.60-3.75 (m, 1H), 4.90-5.15 (m, 1H), 5.10 (s,2H), 7.25-7.45 (m, 5H). LC/MS: condition 1, retention time = 3.63 minLC/MS (ESI⁺) m/z; 302 [M + H]⁺ 128b ¹H-NMR (CDCl₃) δ: 1.41-1.53 (m, 3H),1.53-1.91 (m, 7H), 2.01-2.25 (m, 3H), 3.73-3.86 (m, 1H), 4.98-5.02 (m,1H), 5.10 (s, 2H), 7.28-7.43 (m, 5H). LC/MS: condition 1, retention time= 3.63 min LC/MS (ESI⁺) m/z; 302 [M + H]⁺ 129 ¹H-NMR (DMSO-d₆) δ: 1.20(d, J = 12.3 Hz, 2H), 1.57 (m, 5H), 1.72 (s, 1H), 1.92-1.96 (m, 5H),2.83 (s, 1H), 4.26 (br s, 1H). LC/MS: condition 1, retention time = 0.33min LC/MS (ESI⁺) m/z; 168 [M + H]⁺ 130 ¹H-NMR (DMSO-d₆) δ: 1.27 (d, J =12.7 Hz, 2H), 1.41-1.63 (m, 6H), 1.76-2.02 (m, 5H), 2.75-2.80 (br s,1H). LC/MS: condition 1, retention time = 0.33 min LC/MS (ESI⁺) m/z; 168[M + H]⁺ 131 ¹H-NMR (CD₃OD) δ: 4.03 (dd, J = 13.5, 12.9 Hz, 2H). 132LC/MS: condition 1, retention time = 4.18 min LC/MS (ESI⁺) m/z; 302 [M +H]⁺ 133 ¹H-NMR (CDCl₃) δ: 0.04 (s, 9H), 0.89 (s, 6H), 1.52-1.57 (m, 5H),1.63-1.72 (m, 5H), 3.17 (s, 3H), 3.55 (d, J = 6.9 Hz, 2H), 3.68 (s, 3H).134 ¹H-NMR (CDCl₃) δ: −0.04 (s, 6H), 0.85 (s, 9H), 1.43-1.77 (m, 8H),1.80-1.94 (m, 2H), 3.49 (d, J = 6.9 Hz, 2H), 7.16 (dd, J = 3.6, 2.1 Hz,1H), 7.16 (dd, J = 3.6, 2.7 Hz, 1H), 8.95 (s, 1H), 9.16 (br s, 1H).

TABLE^(a) 94 Rf Data 135a ¹H-NMR (CDCl₃) δ: −0.06 (s, 6H), 0.83 (s, 9H),1.61-2.15 (m, 9H), 3.29-3.37 (m, 1H), 3.56 (d, J = 6.6 Hz, 2H), 6.72(dd, J = 3.3 2.1 Hz, 1H), 7.22 (t, J = 3.3 Hz, 1H), ), 9.04 (s, 2H),9.17 (br s, 1H). LC/MS: condition 3, retention time = 3.22 min LC/MS(ESI⁺) m/z; 386 [M + H]⁺ LC/MS (ESI⁻) m/z; 384 [M − H]⁻ 135b ¹H-NMR(CDCl₃) δ: 0.08 (s, 6H), 0.93 (s, 9H), 1.20 (qd, J = 12.2, 3.6 Hz, 2H),1.76-1.61 (m, 1H), 2.05-1.84 (m, 4H), 2.19-2.09 (m, 2H), 3.16 (tt, J =12.2, 3.6 Hz, 1H), 3.52 (d, J = 6.3 Hz, 2H), 6.81 (dd, J = 3.3, 2.0 Hz,1H), 7.29 (t, J = 3.3 Hz, 1H), 9.21 (br s, 1H), 9.23 (s, 1H). LC/MS:condition 3, retention time = 3.20 min LC/MS (ESI⁺) m/z; 386 [M + H]⁺LC/MS (ESI⁻) m/z; 384 [M − H]⁻ 137 LC/MS: condition 1, retention time =0.32 min LC/MS (ESI⁺) m/z; 201 [M + H]⁺ 138 LC/MS: condition 1,retention time = 0.34 min LC/MS (ESI⁺) m/z; 215 [M + H]⁺ 139 ¹H-NMR(CDCl₃) δ: 1.46 (s, 9H), 4.58-4.65 (m, 2H), 4.68-4.74 (m, 2H), 5.36-5.41(m, 1H). LC/MS: condition 1, retention time = 3.44 min LC/MS (ESI⁺) m/z;195 [M + H]⁺ 140 ¹H-NMR (CDCl₃) δ: 1.56-1.75 (m, 6H), 1.82-1.96 (m, 6H),2.22-2.28 (m, 2H), 3.17 (s, 3H), 3.68 (s, 3H). LC/MS: condition 3,retention time = 2.84 min LC/MS (ESI⁺) m/z; 240 [M + H]⁺ 141 ¹H-NMR(CDCl₃) δ: 1.50-1.97 (m, 8H), 2.10-2.27 (m, 6H), 2.33-2.38 (m, 2H),6.96-6.99 (m, 1H), 7.43-7.47 (m, 1H), 8.93 (s, 1H), 9.25 (br s, 1H).LC/MS: condition 3, retention time = 3.17 min LC/MS (ESI⁺) m/z; 298 [M +H]⁺ LC/MS (ESI⁻) m/z; 296 [M − H]⁻

TABLE^(a) 95 Ex Data 1 ¹H-NMR (CDCl₃) δ: 1.41-1.52 (m, 3H), 1.77-1.91(m, 7H), 2.72 (s, 3H), 2.97-3.05 (m, 1H), 6.64 (d, J = 2.3 Hz, 1H), 7.06(d, J = 2.6 Hz, 1H), 8.29 (s, 1H), 8.80 (br s, 1H). LC/MS: condition 1,retention time = 1.96 min LC/MS (ESI⁺) m/z; 255 [M + H]⁺ 2 ¹H-NMR(CDCl₃) δ: 1.39-1.53 (m, 3H), 1.77-1.95 (m, 7H), 2.95-3.11 (m, 1H), 6.60(d, J = 3.3 Hz, 1H), 7.12 (d, J = 3.0 Hz, 1H), 8.28 (s, 1H), 8.69 (s,1H). LC/MS: condition 1, retention time = 2.84 min LC/MS (ESI⁺) m/z; 241[M + H]⁺ 3 LC/MS: condition 1, retention time = 3.56 min LC/MS (ESI⁺)m/z; 376 [M + H]⁺ 4 LC/MS: condition 1, retention time = 0.96 min LC/MS(ESI⁺) m/z; 309 [M + H]⁺ 5 ¹H-NMR (CDCl₃) δ: 2.46 (s, 3H), 6.60 (dd, J =3.3, 2.4 Hz, 1H), 7.18-7.23 (m, 1H), 7.28-7.43 (m, 3H), 7.54-7.63 (m,1H), 9.04 (br s, 1H), 9.32 (s, 1H). LC/MS: condition 1, retention time =3.87 min LC/MS (ESI⁺) m/z; 250 [M + H]⁺ LC/MS (ESI⁻) m/z; 248 [M − H]⁻ 6¹H-NMR (CDCl₃) δ: 1.31-1.69 (m, 3H), 1.72-1.86 (m, 2H), 1.87-2.01 (m,3H), 2.02-2.16 (m, 2H), 3.07-3.29 (m, 1H), 6.81 (dd, J = 3.3, 2.1 Hz,1H), 7.29 (t, J = 3.0 Hz, 1H), 9.23 (s, 1H), 9.33 (br s, 1H). LC/MS:condition 1, retention time = 3.92 min LC/MS (ESI⁺) m/z; 242 [M + H]⁺LC/MS (ESI⁻) m/z; 240 [M − H]⁻ 7 LC/MS: condition 1, retention time =4.12 min LC/MS (ESI⁺) m/z; 256 [M + H]⁺ LC/MS (ESI⁻) m/z; 254 [M − H]⁻ 8¹H-NMR (DMSO-d₆) δ: 1.15-1.55 (m, 3H), 1.60-1.92 (m, 7H), 2.85-3.10 (m,1H), 6.57 (s, 1H), 7.17 (t, J = 3.0 Hz, 1H), 8.64 (s, 1H), 12.04 (s,1H), 12.96 (br s, 1H). LC/MS: condition 1, retention time = 3.79 minLC/MS (ESI⁺) m/z; 273 [M + H]⁺ LC/MS (ESI⁻) m/z; 271 [M − H]⁻ 9 ¹H-NMR(DMSO-d₆) δ: 1.07-1.64 (m, 5H), 1.65-1.89 (m, 5H), 2.67-2.84 (m, 1H),6.33 (s, 1H), 6.93 (d, J = 2.7 Hz, 1H), 8.01 (d, J = 1.2 Hz, 1H), 10.76(s, 1H), 11.63 (s, 1H). LC/MS: condition 1, retention time = 3.62 minLC/MS (ESI⁺) m/z; 257 [M + H]⁺ 10 ¹H-NMR (CDCl₃) δ: 1.16-1.40 (m, 3H),1.61-1.82 (m, 1H), 1.85-2.09 (m, 4H), 2.10-2.26 (m, 2H), 3.09-3.25 (m,1H), 3.58 (t, J = 6.0 Hz, 2H), 6.74-6.85 (m, 1H), 7.20-7.32 (m, 1H),9.04 (br s, 1H), 9.22 (s, 1H). LC/MS: condition 1, retention time = 2.99min LC/MS (ESI⁺) m/z; 272 [M + H]⁺ LC/MS (ESI⁻) m/z; 270 [M − H]⁻

TABLE^(a) 96 Ex Data 11 ¹H-NMR (CDCl₃) δ: 0.86 (d, J = 6.5 Hz, 3H), 1.48(br s, 9H), 1.87 (d, J = 12.3 Hz, 1H), 2.04-2.11 (m, 1H), 2.23-2.39 (m,2H), 2.92 (td, J = 11.0, 4.5 Hz, 2H), 3.17 (t, J = 11.0 Hz, 1H), 3.48(d, J = 7.0 Hz, 1H), 7.24-7.32 (m, 2H), 9.18 (br s, 1H), 9.22 (s, 1H).LC/MS: condition 1, retention time = 4.05 min LC/MS (ESI⁺) m/z; 301 [M −^(t)Bu]⁺ LC/MS (ESI⁻) m/z; 355 [M − H]⁻ 12 LC/MS: condition 1, retentiontime = 3.09 min LC/MS (ESI⁺) m/z; 324 [M + H]⁺ 13 ¹H-NMR (CDCl₃) δ:1.18-1.29 (m, 1H), 1.49 (s, 9H), 1.63-1.77 (m, 1H), 1.90 (dt, J = 13.9,3.0 Hz, 1H), 2.09-2.33 (m, 2H), 2.87 (t, J = 13.2 Hz, 1H), 3.30 (tt, J =11.6, 4.3 Hz, 1H), 4.23 (br s, 1H), 4.44 (br s, 1H), 6.92 (br s, 1H),7.31 (t, J = 3.3 Hz, 1H), 9.23 (s, 1H), 9.27 (br s, 1H). LC/MS:condition 1, retention time = 3.79 min LC/MS (ESI⁺) m/z; 287 [M −^(t)Bu]⁺ LC/MS (ESI⁻) m/z; 341 [M − H]⁻ 14 ¹H-NMR (CDCl₃) δ: 1.68-1.80(m, 1H), 1.93 (d, J = 13.5 Hz, 1H), 2.14-2.37 (m, 2H), 2.95 (br s, 1H),3.07-3.22 (m, 1H), 3.26-3.38 (m, 1H), 4.33 (br s, 1H), 4.55 (br s, 1H),5.20 (d, J = 5.9 Hz, 2H), 6.95-7.17 (m, 1H), 7.28-7.43 (m, 6H), 9.22 (s,1H), 9.39 (br s, 1H). LC/MS: condition 1, retention time = 3.84 minLC/MS (ESI⁺) rn/z; 377 [M + H]⁺ LC/MS (ESI⁻) m/z; 375 [M − H]⁻ 15 ¹H-NMR(CD₃OD) δ: 1.71-1.93 (m, 3H), 2.01-2.24 (m, 2H), 2.70-2.81 (m, 1H),2.94-3.17 (m, 2H), 3.37-3.47 (m, 1H), 6.91 (d, J = 3.3 Hz, 1H), 7.41 (d,J = 3.0 Hz, 1H), 9.32 (s, 1H). LC/MS: condition 1, retention time = 0.35min LC/MS (ESI⁺) m/z; 243 [M + H]⁺ LC/MS (ESI⁻) m/z; 241 [M − H]⁻ 16LC/MS: condition 1, retention time = 0.40 min LC/MS (ESI⁺) m/z; 333 [M +H]⁺ 17 LC/MS: condition 1, retention time = 3.25 min LC/MS (ESI⁺) m/z;353 [M + H]⁺ LC/MS (ESI⁻) m/z; 351 [M − H]⁻ 18 ¹H-NMR (CDCl₃) δ:1.23-1.35 (m, 4H), 1.85-1.96 (m, 2H), 2.20 (m, 1H), 2.50 (t, J = 11.6Hz, 1H), 3.01 (d, J = 10.9 Hz, 1H), 3.16 (d, J = 10.9 Hz, 1H), 3.41-3.53(m, 1H), 6.71 (dd, J = 3.3, 2.0 Hz, 1H), 7.22-7.31 (m, 2H), 7.70 (d, J =7.6 Hz, 1H), 8.50 (dd, J = 4.6, 2.0 Hz, 1H), 8.60 (d, J = 2.0 Hz, 1H),9.21 (s, 1H), 9.32 (br s, 1H). LC/MS: condition 1, retention time = 0.35min LC/MS (ESI⁺) m/z; 334 [M + H]⁺ LC/MS (ESI⁻) m/z; 332 [M − H]⁻

TABLE^(a) 97 Ex Data 19 ¹H-NMR (CDCl₃) δ: 1.23-1.29 (m, 1H), 1.85-1.96(m, 3H), 2.13-2.27 (m, 2H), 2.49 (t, J = 11.2 Hz, 1H), 3.05 (d, J = 10.2Hz, 1H), 3.20 (d, J = 10.9 Hz, 1H), 3.41-3.53 (m, 1H), 6.75 (dd, J =3.3, 2.0 Hz, 1H), 7.23-7.29 (m, 1H), 8.74 (s, 1H), 9.19 (br s, 1H), 9.21(s, 1H). LC/MS: condition 1, retention time = 0.35 min LC/MS (ESI⁺) m/z;340 [M + H]⁺ LC/MS (ESI⁻) m/z; 338 [M − H]⁻ 20 ¹H-NMR (DMSO-d₆) δ:1.62-1.79 (t, J = 12.6 Hz, 1H), 1.81-1.92 (m, 1H), 1.95-2.11 (m, 1H),2.12-2.24 (m, 1H), 3.07 (t, J = 12.6 Hz, 1H), 3.21 (m, 1H), 4.37 (d, J =12.6 Hz, 1H), 4.57 (d, J = 11.6 Hz, 1H), 6.99 (s, 1H), 7.53 (s, 1H),8.95 (br s, 1H), 9.56-9.60 (m, 1H), 12.59 (s, 1H). LC/MS: condition 1,retention time = 2.94 min LC/MS (ESI⁺) m/z; 370 [M + H]⁺ LC/MS (ESI⁻)m/z; 368 [M − H]⁻ 21 ¹H-NMR (DMSO-d₆) δ: 1.64-1.79 (m, 1H), 1.82-2.06(m, 2H), 2.13-2.22 (m, 1H), 2.25 (s, 3H), 3.07 (t, J = 12.2 Hz, 1H),4.22 (d, J = 13.2 Hz, 1H), 4.43 (d, J = 12.9 Hz, 1H), 6.59 (s, 1H), 6.98(d, J = 2.6 Hz, 1H), 7.53 (d, J = 3.3 Hz, 1H), 9.57 (s, 1H), 10.46 (brs, 1H), 12.58 (br s, 1H). LC/MS: condition 1, retention time = 2.90 minLC/MS (ESI⁺) m/z; 383 [M + H]⁺ LC/MS (ESI⁻) m/z; 381 [M − H]⁻ 22 ¹H-NMR(CDCl₃) δ: 1.26 (t, J = 7.3 Hz, 1H), 1.86-2.01 (m, 2H), 2.15-2.27 (m,2H), 2.47 (t, J = 11.2 Hz, 1H), 2.98 (d, J = 11.2 Hz, 1H), 3.11 (dt, J =11.2, 1.7 Hz, 1H), 3.40-3.51 (m, 1H), 3.57 (d, J = 13.9 Hz, 1H), 3.69(d, J = 13.9 Hz, 1H), 6.66 (dd, J = 3.3, 2.0 Hz, 1H), 7.25-7.28 (m, 1H),7.49 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 7.9 Hz, 2H), 9.17 (br s, 1H),9.21 (s, 1H). LC/MS: condition 1, retention time = 0.59 min LC/MS (ESI⁺)m/z; 358 [M + H]⁺ LC/MS (ESI⁻) m/z; 356 [M − H]⁻ 23 ¹H-NMR (CDCl₃) δ:1.23-1.32 (m, 1H), 1.81-1.98 (m, 2H), 2.15-2.27 (m, 2H), 2.42 (t, J =11.2 Hz, 1H), 3.01 (d, J = 10.9 Hz, 1H), 3.15 (d, J = 10.6 Hz, 1H), 3.45(td, J = 11.6, 3.0 Hz, 1H), 3.56 (d, J = 13.2 Hz, 1H), 3.71 (d, J = 13.2Hz, 1H), 6.58-6.62 (m, 1H), 7.20-7.24 (m, 1H), 7.48 (d, J = 7.9 Hz, 2H),7.56 (d, J = 7.9 Hz, 2H), 9.21 (s, 2H). LC/MS: condition 1, retentiontime = 2.49 min LC/MS (ESI⁺) m/z; 401 [M + H]⁺ LC/MS (ESI⁻) m/z; 399 [M− H]⁻ 24 ¹H-NMR (CDCl₃) δ: 1.51 (s, 9H), 1.95-2.20 (m, 4H), 2.85-3.10(m, 2H), 3.29-3.48 (m, 1H), 4.15-4.42 (m, 2H), 6.71-6.80 (m, 1H),7.27-7.35 (m, 1H), 9.23 (s, 1H), 9.27 (br s, 1H). LC/MS: condition 1,retention time = 3.94 min LC/MS (ESI⁺) m/z; 343 [M − ^(t)Bu]⁺ LC/MS(ESI⁻) m/z; 341 [M − H]⁻

TABLE^(a) 98 Ex Data 25 ¹H-NMR (CDCl₃) δ: 1.99-2.10 (m, 2H), 2.39 (dq, J= 11.7, 3.9 Hz, 2H), 2.65 (dt, J = 11.7, 2.4 Hz, 2H), 3.09 (q, J = 9.6Hz, 2H), 3.11-3.29 (m, 3H), 6.85 (dd, J = 2.5, 0.9 Hz, 1H), 7.31 (dd, J= 3.0, 0.9 Hz, 1H), 9.11 (br s, 1H), 9.23 (s, 1H). LC/MS: condition 1,retention time = 2.30 min LC/MS (ESI⁺) m/z; 325 [M + H]⁺ LC/MS (ESI⁻)m/z; 323 [M − H]⁻ 26 ¹H-NMR (CDCl₃) δ: 2.00-2.15 (m, 4H), 3.01-3.18 (m,2H), 3.32-3.45 (m, 1H), 4.30-4.44 (m, 2H), 5.19 (s, 2H), 6.70-6.76 (m,1H), 7.25-7.43 (m, 6H), 9.18 (br s, 1H), 9.22 (s, 1H). LC/MS: condition1, retention time = 3.79 min LC/MS (ESI⁺) m/z; 377 [M + H]⁺ LC/MS (ESI⁻)m/z; 375 [M − H]⁻ 27 ¹H-NMR (CD₃OD) δ: 2.05-2.15 (m, 4H), 2.90-3.13 (m,2H), 3.38-3.50 (m, 1H), 6.93 (d, J = 3.3 Hz, 1H), 7.40 (d, J = 3.3 Hz,1H), 9.31 (s, 1H). LC/MS: condition 1, retention time = 0.44 min LC/MS(ESI⁺) m/z; 243 [M + H]⁺ LC/MS (ESI⁻) m/z; 241 [M − H]⁻ 28 ¹H-NMR(CDCl₃) δ: 1.95-2.12 (m, 2H), 2.12-2.31 (m, 4H), 2.99-3.12 (m, 2H),3.17-3.31 (m, 1H), 3.61 (s, 2H), 6.85 (d, J = 2.4 Hz, 1H), 7.23-7.35 (m,2H), 7.74 (d, J = 7.8 Hz, 1H), 8.52 (dd, J = 4.5, 1.2 Hz, 1H), 8.62 (d,J = 2.1 Hz, 1H), 9.22 (s, 1H), 9.39 (br s, 1H). LC/MS: condition 3,retention time = 0.52 min LC/MS (ESI⁺) m/z; 334 [M + H]⁺ LC/MS (ESI⁻)m/z; 332 [M − H]⁻ 29 ¹H-NMR (DMSO-d₆) δ: 1.64-1.82 (m, 1H), 1.86-2.04(m, 3H), 2.85-3.00 (m, 1H), 3.30-3.39 (m, 1H), 3.45-3.60 (m, 1H),3.61-3.84 (m, 2H), 3.92-4.05 (m, 1H), 4.43-4.55 (m, 1H), 6.82-6.90 (m,1H), 7.49-7.53 (m, 1H), 9.53 (s, 1H), 12.51 (br s, 1H). LC/MS: condition3, retention time = 1.62 min LC/MS (ESI⁺) m/z; 353 [M + H]⁺ LC/MS (ESI⁻)m/z; 351 [M − H]⁻ 30 ¹H-NMR (DMSO-d₆) δ: 1.70-2.10 (m, 4H), 3.09-3.26(m, 2H), 3.43-3.65 (m, 1H), 4.14-4.50 (m, 2H), 6.85 (s, 1H), 7.49 (s,1H), 9.00 (br s, 1H), 9.53 (s, 1H), 11.34 (br s, 1H), 12.54 (br s, 1H).LC/MS: condition 3, retention time = 1.40 min LC/MS (ESI⁺) m/z; 370 [M +H]⁺ LC/MS (ESI⁻) m/z; 368 [M − H]⁻ 31 ¹H-NMR (DMSO-d₆) δ: 1.70-2.10 (m,4H), 2.27 (s, 3H), 3.10-3.26 (m, 2H), 3.43-3.64 (m, 1H), 4.15-4.41 (m,2H), 6.63 (s, 1H), 6.83-6.89 (m, 1H), 7.45-7.52 (m, 1H), 9.54 (s, 1H),10.48 (s, 1H), 12.55 (br s, 1H). LC/MS: condition 3, retention time =1.43 min LC/MS (ESI⁺) m/z; 383 [M + H]⁺ LC/MS (ESI⁻) m/z; 381 [M − H]⁻

TABLE^(a) 99 Ex Data 32 ¹H-NMR (DMSO-d₆) δ: 1.85-2.08 (m, 4H), 2.13-2.30(m, 2H), 2.90-3.03 (m, 2H), 3.11-3.25 (m, 1H), 3.55 (s, 2H), 6.81 (s,1H), 7.20-7.40 (m, 5H), 7.49 (s, 1H), 9.52 (s, 1H), 12.53 (br s, 1H).LC/MS: condition 3, retention time = 1.31 min LC/MS (ESI⁺) m/z; 333 [M +H]⁺ 33 ¹H-NMR (DMSO-d₆) δ: 1.87-2.11 (m, 4H), 2.18-2.31 (m, 2H),2.88-3.02 (m, 2H), 3.12-3.26 (m, 1H), 3.65 (s, 2H), 6.83 (s, 1H), 7.49(m, 1H), 7.60 (d, J = 8.3 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 9.52 (s,1H), 12.53 (br s, 1H). LC/MS: condition 3, retention time = 1.63 minLC/MS (ESI⁺) m/z; 401 [M + H]⁺ 34 ¹H-NMR (DMSO-d₆) δ: 1.85-2.10 (m, 4H),2.19-2.33 (m, 2H), 2.87-3.00 (m, 2H), 3.10-3.26 (m, 1H), 3.65 (s, 2H),6.82 (d, J = 3.0 Hz, 1H), 7.49 (d, J = 3.0 Hz, 1H), 7.58 (d, J = 8.2 Hz,2H), 7.81 (d, J = 8.2 Hz, 2H), 9.52 (s, 1H), 12.53 (br s, 1H). LC/MS:condition 3, retention time = 1.23 min LC/MS (ESI⁺) m/z; 358 [M + H]⁺LC/MS (ESI⁻) m/z; 356 [M − H]⁻ 35 ¹H-NMR (DMSO-d₆) δ: 1.85-2.10 (m, 4H),2.18-2.31 (m, 2H), 2.87-2.99 (m, 2H), 3.13-3.23 (m, 1H), 3.62 (s, 2H),6.83 (s, 1H), 7.49 (s, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.67-7.77 (m, 2H),7.94 (s, 1H), 9.52 (s, 1H), 12.53 (br s, 1H). LC/MS: condition 3,retention time = 1.24 min LC/MS (ESI⁺) m/z; 358 [M + H]⁺ LC/MS (ESI⁻)m/z; 356 [M − H]⁻ 36 ¹H-NMR (DMSO-d₆) δ: 1.85-2.05 (m, 4H), 2.10-2.30(m, 2H), 2.24 (s, 3H), 2.36 (s, 3H), 2.85-2.99 (m, 2H), 3.10-3.27 (m,1H), 6.79 (d, J = 3.2 Hz, 1H), 7.49 (d, J = 3.2 Hz, 1H), 9.52 (s, 1H),12.53 (br s, 1H). LC/MS: condition 3, retention time = 1.07 min LC/MS(ESI⁺) m/z; 352 [M + H]⁺ LC/MS (ESI⁻) m/z; 350 [M − H]⁻ 37 ¹H-NMR(DMSO-d₆) δ: 1.86-2.08 (m, 4H), 2.16-2.29 (m, 2H), 2.88-3.00 (m, 2H),3.10-3.25 (m, 1H), 3.58 (s, 2H), 6.82 (d, J = 3.0 Hz, 1H), 7.34 (d, J =8.4 Hz, 2H), 7.46-7.55 (m, 3H), 9.53 (s, 1H), 12.54 (br s, 1H). LC/MS:condition 3, retention time = 1.69 min LC/MS (ESI⁺) m/z; 417 [M + H]⁺LC/MS (ESI⁻) m/z; 415 [M − H]⁻ 38 ¹H-NMR (DMSO-d₆) δ: 1.87-2.06 (m, 4H),2.16-2.30 (m, 2H), 2.90-3.03 (m, 2H), 3.12-3.25 (m, 1H), 3.63 (s, 2H),6.80-6.85 (m, 1H), 7.49-7.53 (m, 1H), 7.55 (d, J = 7.8 Hz, 2H), 7.70 (d,J = 7.8 Hz, 2H), 9.53 (s, 1H), 12.54 (br s, 1H). LC/MS: condition 3,retention time = 1.78 min LC/MS (ESI⁺) m/z; 433 [M + H]⁺ LC/MS (ESI⁻)m/z; 431 [M − H]⁻

TABLE^(a) 100 Ex Data 39 ¹H-NMR (DMSO-d₆) δ: 1.85-2.15 (m, 4H),2.20-2.38 (m, 2H), 2.88-3.08 (m, 2H), 3.12-3.27 (m, 1H), 3.66 (s, 2H),6.82 (d, J = 3.0 Hz, 1H), 7.49 (s, 1H), 7.52-7.80 (m, 4H), 9.52 (s, 1H),12.53 (br s, 1H). LC/MS: condition 3, retention time = 1.60 min LC/MS(ESI⁺) m/z; 401 [M + H]⁺ LC/MS (ESI⁻) m/z; 399 [M − H]⁻ 40 ¹H-NMR(DMSO-d₆) δ: 1.95-2.09 (m, 4H), 2.27-2.33 (m, 2H), 2.96 (d, J = 11.4 Hz,2H), 3.15-3.20 (m, 1H), 3.69 (s, 2H), 6.82 (dd, J = 3.2, 1.4 Hz, 1H),7.50 (t, J = 2.9 Hz, 1H), 7.72 (d, J = 4.2 Hz, 2H), 7.84 (d, J = 9.9 Hz,1H), 9.53 (s, 1H), 12.54 (br s, 1H). LC/MS: condition 3, retention time= 1.28 min LC/MS (ESI⁺) m/z; 376 [M + H]⁺ LC/MS (ESI⁻) m/z; 374 [M − H]⁻41 ¹H-NMR (DMSO-d₆) δ: 1.85-2.05 (m, 4H), 2.14-2.30 (m, 2H), 2.86-3.00(m, 2H), 3.10-3.25 (m, 1H), 3.53 (s, 2H), 6.79-6.86 (m, 1H), 7.33 (d, J= 8.3 Hz, 2H), 7.44-7.52 (m, 1H), 7.53 (d, J = 8.3 Hz, 2H), 9.52 (s,1H), 12.53 (br s, 1H). LC/MS: condition 3, retention time = 1.58 minLC/MS (ESI⁺) m/z; 411, 413 [M + H]⁺ 42 ¹H-NMR (DMSO-d₆) δ: 2.15-2.37 (m,4H), 3.16-3.30 (m, 3H), 3.36-3.50 (m, 3H), 3.50-3.73 (m, 1H), 3.79-3.82(m, 2H), 7.07 (br s, 1H), 7.53-7.62 (m, 3H), 7.70-7.79 (m, 2H), 9.57 (s,1H), 9.75-9.98 (br s, 1H), 12.61 (br s, 1H). LC/MS: condition 3,retention time = 1.79 min LC/MS (ESI⁺) m/z; 415 [M + H]⁺ LC/MS (ESI⁻)m/z; 413 [M − H]⁻ 43 ¹H-NMR (DMSO-d₆) δ: 1.94-2.06 (m, 4H), 2.20 (td, J= 10.8, 3.3 Hz, 2H), 2.94 (d, J = 11.7 Hz, 2H), 3.18 (septet, J = 5.2Hz, 1H), 3.54 (s, 2H), 6.82 (d, J = 3.3 Hz, 1H), 7.16 (tt, J = 9.2, 2.5Hz, 2H), 7.40 (dd, J = 8.4, 5.7 Hz, 2H), 7.50 (d, J = 3.3 Hz, 1H), 9.52(s, 1H), 12.53 (br s, 1H). LC/MS: condition 3, retention time = 1.49 minLC/MS (ESI⁺) m/z; 351 [M + H]⁺ LC/MS (ESI⁻) m/z; 349 [M − H]⁻ 44 ¹H-NMR(DMSO-d₆) δ: 1.86-2.08 (m, 4H), 2.20-2.35 (m, 2H), 2.92-3.06 (m, 2H),3.10-3.25 (m, 1H), 3.84 (s, 2H), 6.82 (d, J = 3.3 Hz, 1H), 7.49 (d, J =3.3 Hz, 1H), 7.80 (s, 1H), 9.03 (s, 1H), 9.52 (s, 1H), 12.53 (br s, 1H).LC/MS: condition 3, retention time = 0.62 min LC/MS (ESI⁺) m/z; 340 [M +H]⁺ LC/MS (ESI⁻) m/z; 338 [M − H]⁻ 45 ¹H-NMR (DMSO-d₆) δ: 1.73-1.88 (m,2H), 1.88-2.12 (m, 4H), 2.14-2.32 (m, 2H), 2.33-2.50 (m, 2H), 2.59-2.71(m, 2H), 2.98-3.13 (m, 2H), 3.14-3.25 (m, 1H), 6.82 (s, 1H), 7.10-7.36(m, 5H), 7.49 (s, 1H), 9.52 (s, 1H), 12.53 (br s, 1H). LC/MS: condition3, retention time = 1.55 min LC/MS (ESI⁺) m/z; 361 [M + H]⁺ LC/MS (ESI⁻)m/z; 359 [M − H]⁻

TABLE^(a) 101 Ex Data 46 ¹H-NMR (DMSO-d₆) δ: 1.91-2.05 (m, 4H),2.16-2.23 (m, 2H), 2.94 (d, J = 11.4 Hz, 2H), 3.14-3.21 (m, 1H), 3.50(s, 2H), 3.83 (s, 3H), 6.82 (t, J = 2.4 Hz, 1H), 7.12-7.20 (m, 3H), 7.50(t, J = 2.7 Hz, 1H), 9.53 (s, 1H), 12.54 (br s, 1H). LC/MS: condition 3,retention time = 1.39 min LC/MS (ESI⁺) m/z; 381 [M + H]⁺ 47 ¹H-NMR(DMSO-d₆) δ: 1.85-2.09 (m, 4H), 2.22-2.39 (m, 2H), 2.88-3.03 (m, 2H),3.12-3.25 (m, 1H), 3.78 (s, 2H), 6.84 (d, J = 2.8 Hz, 1H), 7.49 (d, J =2.8 Hz, 1H), 8.00 (s, 1H), 8.07 (s, 2H), 9.52 (s, 1H), 12.55 (br s, 1H).LC/MS: condition 3, retention time = 1.84 min LC/MS (ESI⁺) m/z; 469 [M +H]⁺ LC/MS (ESI⁻) m/z; 467 [M − H]⁻ 48 ¹H-NMR (DMSO-d₆) δ: 1.88-2.13 (m,4H), 2.32-2.46 (m, 2H), 2.97-3.10 (m, 2H), 3.14-3.27 (m, 1H), 3.91 (s,2H), 6.85 (d, J = 3.0 Hz, 1H), 7.51 (d, J = 3.0 Hz, 1H), 7.67 (d, J =3.3 Hz, 1H), 7.72 (d, J = 3.3 Hz, 1H), 9.52 (s, 1H), 12.55 (br s, 1H).LC/MS: condition 3, retention time = 0.91 min LC/MS (ESI⁺) m/z; 340 [M +H]⁺ LC/MS (ESI⁻) m/z; 338 [M − H]⁻ 49 ¹H-NMR (DMSO-d₆) δ: 1.87-2.07 (m,4H), 2.18-2.34 (m, 2H), 2.94-3.08 (m, 2H), 3.12-3.34 (m, 1H), 3.71 (s,2H), 6.82 (d, J = 3.3 Hz, 1H), 6.87 (d, J = 3.3 Hz, 1H), 6.96 (d, J =3.6 Hz, 1H), 7.50 (d, J = 3.6 Hz, 1H), 9.52 (s, 1H), 12.55 (br s, 1H).LC/MS: condition 3, retention time = 1.49 min LC/MS (ESI⁺) m/z; 373, 375[M + H]⁺ LC/MS (ESI⁻) m/z; 371, 373 [M − H]⁻ 50 ¹H-NMR (DMSO-d₆) δ:0.78-0.98 (m, 2H), 1.12-1.32 (m, 3H), 1.59-1.72 (m, 2H), 1.72-1.85 (m,2H), 1.85-2.04 (m, 4H), 2.04-2.23 (m, 3H), 2.67-2.78 (m, 2H), 2.88-3.05(m, 3H), 3.08-3.21 (m, 1H), 6.79 (s, 1H), 7.49 (s, 1H), 9.52 (s, 1H),12.52 (br s, 1H). LC/MS: condition 3, retention time = 1.51 min LC/MS(ESI⁺) m/z; 339 [M + H]⁺ LC/MS (ESI⁻) m/z; 337 [M − H]⁻ 51 ¹H-NMR(DMSO-d₆) δ: 1.32-1.70 (m, 6H), 1.77-2.05 (m, 6H), 2.06-2.30 (m, 2H),3.04-3.23 (m, 3H), 6.80 (d, J = 3.0 Hz, 1H), 7.49 (s, 1H), 9.52 (s, 1H),12.53 (br s, 1H). LC/MS: condition 3, retention time = 1.18 min LC/MS(ESI⁺) m/z; 311 [M + H]⁺ 52 ¹H-NMR (DMSO-d₆) δ: 1.86-2.10 (m, 4H),2.23-2.35 (m, 2H), 2.90-3.03 (m, 2H), 3.14-3.27 (m, 1H), 3.71 (s, 2H),6.83 (d, J = 3.3 Hz, 1H), 7.49 (d, J = 3.3 Hz, 1H), 7.89 (d, J = 8.1 Hz,1H), 8.07 (d, J = 9.3 Hz, 1H), 8.75 (s, 1H), 9.52 (s, 1H), 12.53 (br s,1H). LC/MS: condition 3, retention time = 1.40 min LC/MS (ESI⁺) m/z; 402[M + H]⁺ LC/MS (ESI⁻) m/z; 400 [M − H]⁻

TABLE^(a) 102 Ex Data 53 ¹H-NMR (DMSO-d₆) δ: 1.90-1.97 (m, 4H),2.26-2.34 (m, 2H), 2.93-2.97 (m, 2H), 3.13 (quint, J = 6.2 Hz, 1H), 3.72(s, 2H), 6.80 (dd, J = 2.9 Hz, 1.7 Hz, 1H), 7.47 (t, J = 2.9 Hz, 1H),7.81 (s, 1H), 7.84 (s, 1H), 9.51 (s, 1H), 12.51 (br s, 1H). LC/MS:condition 3, retention time = 1.26 min LC/MS (ESI⁺) m/z; 394 [M + H]⁺ 54¹H-NMR (DMSO-d₆) δ: 1.95-2.02 (m, 4H), 2.18-2.24 (m, 2H), 2.94 (d, J =11.4 Hz, 2H), 3.55 (s, 2H), 6.79 (d, J = 3.0 Hz, 1H), 7.40 (s, 4H), 7.48(d, J = 3.0 Hz, 1H), 9.48 (s, 1H). LC/MS: condition 3, retention time =1.75 min LC/MS (ESI⁺) m/z; 367, 369 [M + H]⁺ LC/MS (ESI⁻) m/z; 365, 367[M − H]⁻ 55 ¹H-NMR (DMSO-d₆) δ: 1.95-2.03 (m, 4H), 2.19-2.27 (m, 2H),2.95 (d, J = 12.0 Hz, 2H), 3.58 (s, 2H), 6.80 (d, J = 2.7 Hz, 1H),7.05-7.22 (m, 3H), 7.35-7.42 (m, 1H), 7.48 (d, J = 3.3 Hz, 1H), 9.49 (s,1H). LC/MS: condition 3, retention time = 1.61 min LC/MS (ESI⁺) m/z; 351[M + H]⁺  56a ¹H-NMR (DMSO-d₆) δ: 1.20-1.52 (m, 4H), 1.86-2.10 (m, 8H),2.16-2.41 (m, 3H), 2.63-2.80 (m, 1H), 2.88-3.24 (m, 3H), 6.84 (br s,1H), 7.46-7.53 (m, 1H), 9.52 (s, 1H), 12.53 (br s, 1H). LC/MS: condition3, retention time = 1.57 min LC/MS (ESI⁺) m/z; 393 [M + H]⁺ LC/MS (ESI⁻)m/z; 391 [M − H]⁻  56b ¹H-NMR (DMSO-d₆) δ: 1.40-1.66 (m, 4H), 1.66-1.85(m, 2H), 1.92-2.18 (m, 8H), 2.34-2.40 (m, 1H), 2.65-2.77 (m, 1H),3.08-3.28 (m, 3H), 6.78-6.84 (m, 1H), 7.45-7.56 (m, 1H), 9.52 (s, 1H),12.53 (br s, 1H). LC/MS: condition 3, retention time = 1.53 min LC/MS(ESI⁺) m/z; 393 [M + H]⁺ LC/MS (ESI⁻) m/z; 391 [M − H]⁻ 57 ¹H-NMR(DMSO-d₆) δ: 1.83-2.10 (m, 4H), 3.06-3.22 (m, 2H), 3.43-3.60 (m, 1H),4.20-4.35 (m, 2H), 6.86 (d, J = 3.3 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H),7.42-7.53 (m, 2H), 7.79 (d, J = 8.1 Hz, 1H), 7.97 (s, 1H), 8.94 (s, 1H),9.54 (s, 1H), 12.57 (br s, 1H). LC/MS: condition 3, retention time =2.14 min LC/MS (ESI⁺) m/z; 430 [M + H]⁺ LC/MS (ESI⁻) m/z; 428 [M − H]⁻58 ¹H-NMR (DMSO-d₆) δ: 1.93-2.07 (m, 4H), 3.17 (br s, 1H), 3.56-3.62 (m,2H), 4.58 (br s, 1H), 6.86 (d, J = 3.0 Hz, 1H), 7.50 (d, J = 3.0 Hz,1H), 7.68 (d, J = 8.1 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H), 9.50 (s, 1H).LC/MS: condition 3, retention time = 2.13 min LC/MS (ESI⁺) m/z; 415 [M +H]⁺ LC/MS (ESI⁻) m/z; 413 [M − H]⁻

TABLE^(a) 103 Ex Data 59 ¹H-NMR (CDCl₃) δ: 1.20-1.42 (m, 4H), 1.48 (s,9H), 1.92-2.30 (m, 5H), 3.10-3.25 (m, 1H), 3.63 (br s, 1H), 4.47 (br s,1H), 6.79 (dd, J = 3.3, 1.8 Hz, 1H), 7.29 (dd, J = 3.3, 1.8 Hz, 1H),9.22 (s, 1H). LC/MS: condition 1, retention time = 3.74 min LC/MS (ESI⁺)m/z; 357 [M + H]⁺ LC/MS (ESI⁻) m/z; 355 [M − H]⁻ 60 ¹H-NMR (DMSO-d₆) δ:1.18 (d, J = 6.6 Hz, 1H), 1.38-1.57 (m, 2H), 1.71-1.90 (m, 2H),1.91-2.10 (m, 4H), 3.05-3.20 (m, 1H), 3.37-3.54 (m, 1H), 5.03 (s, 2H),6.81 (d, J = 3.3 Hz, 1H), 7.26-7.42 (m, 5H), 7.48 (d, J = 3.3 Hz, 1H),9.51 (s, 1H), 12.51 (br s, 1H). LC/MS: condition 3, retention time =2.10 min LC/MS (ESI⁺) m/z; 391 [M + H]⁺ 61 LC/MS: condition 3, retentiontime = 0.50 min LC/MS (ESI⁺) m/z; 257 [M + H]⁺ 62 ¹H-NMR (CDCl₃) δ:1.15-1.35 (m, 2H), 1.70-1.85 (m, 1H), 1.86-2.07 (m, 4H), 2.08-2.23 (m,2H), 3.09-3.25 (m, 1H), 3.30 (d, J = 6.3 Hz, 2H), 3.38 (s, 3H),6.73-6.83 (m, 1H), 7.21-7.33 (m, 1H), 9.02 (br s, 1H), 9.21 (s, 1H).LC/MS: condition 1, retention time = 3.57 min LC/MS (ESI⁺) m/z; 286 [M +H]⁺ LC/MS (ESI⁻) m/z; 284 [M − H]⁻ 63 ¹H-NMR (CDCl₃) δ: 1.46, (m, 2H),1.95 (m, 2H), 2.24 (m, 4H), 3.18 (tt, J = 12.0, 3.3 Hz, 1H), 3.34 (tt, J= 10.8, 3.9 Hz, 1H), 3.43 (s, 3H), 6.79 (m, 1H),, 7.30 (m, 1H), 9.22 (s,1H), 9.31 (br s, 1H) LC/MS: condition 1, retention time = 3.13 min LC/MS(ESI⁺) m/z; 272 [M + H]⁺ LC/MS (ESI⁻) m/z; 270 [M − H]⁻ 64 ¹H-NMR(CDCl₃) δ: 1.83-2.43 (m, 8H), 3.27-3.45 (m, 1H), 6.81 (dd, J = 3.3, 2.1Hz, 1H), 7.28-7.39 (m, 1H), 9.24 (s, 1H), 9.25 (br s, 1H). LC/MS:condition 1, retention time = 3.59 min LC/MS (ESI⁺) m/z; 278 [M + H]⁺LC/MS (ESI⁻) m/z; 276 [M − H]⁻ 65 ¹H-NMR (CDCl₃) δ: 1.23-1.87 (m, 7H),2.46 (m, 2H), 2.57 (s, 1H), 3.22 (m, 1H), 6.80 (m, 1H), 7.29 (t, J = 3.3Hz, 1H), 9.17 (br s, 1H), 9.22 (s, 1H). LC/MS: condition 1, retentiontime = 3.89 min LC/MS (ESI⁺) m/z; 254 [M + H]⁺ LC/MS (ESI⁻) m/z; 252 [M− H]⁻ 66 ¹H-NMR (CDCl₃) δ: 1.67-1.75 (m, 6H), 1.92 (m, 2H), 2.06-2.14(m, 4H), 3.40 (tt, J = 9.6, 4.8 Hz, 1H), 6.80 (m, 1H), 7.27 (t, J = 2.7Hz, 1H), 9.03 (br s, 1H), 9.21 (s, 1H). LC/MS: condition 1, retentiontime = 3.94 min LC/MS (ESI⁺) m/z; 256 [M + H]⁺ LC/MS (ESI⁻) m/z; 254 [M− H]⁻

TABLE^(a) 104 Ex Data 67 ¹H-NMR (CDCl₃) δ: 2.06-2.27 (m, 2H), 2.45-2.72(m, 4H), 4.05 (quin t, 8.4 Hz, 1H), 6.80 (dd, J = 3.3, 2.1, 1H), 7.29(t, J = 2.7 Hz, 1H), 9.17 (br s, 1H), 9.22 (s, 1H). LC/MS: condition 1,retention time = 3.34 min LC/MS (ESI⁺) m/z; 214 [M + H]⁺ LC/MS (ESI⁻)m/z; 212 [M − H]⁻ 68 ¹H-NMR (CDCl₃) δ: 1.60-2.08 (m, 8H), 3.71 (quin t,J = 9.0 Hz, 1H), 7.02 (dd, J = 3.3, 2.1, 1H), 7.34 (dd, J = 3.6, 2.4 Hz,1H), 8.88 (s, 1H), 10.05 (br s, 1H). 69 ¹H-NMR (DMSO-d₆) δ: 1.50-1.70(m, 2H), 1.71-1.92 (m, 2H), 1.93-2.18 (m, 4H), 2.30-2.67 (m, 1H),3.15-3.38 (m, 1H), 6.87-7.00 (m, 1H), 7.40-7.55 (m, 1H), 9.52 (s, 1H),12.52 (br s, 1H). LC/MS: condition 1, retention time = 3.97 min LC/MS(ESI⁺) m/z; 310 [M + H]⁺ LC/MS (ESI⁻) m/z; 308 [M − H]⁻ 70 ¹H-NMR(DMSO-d₆) δ: 1.49-1.70 (m, 2H), 1.72-1.93 (m, 2H), 1.95-2.15 (m, 4H),2.36-2.66 (m, 1H), 3.14-3.39 (m, 1H), 6.93 (dd, J = 3.3, 1.8 Hz, 1H),7.42-7.55 (m, 1H), 9.52 (s, 1H), 12.52 (br s, 1H). LC/MS: condition 1,retention time = 3.95 min LC/MS (ESI⁺) m/z; 310 [M + H]⁺ LC/MS (ESI⁻)m/z; 308 [M − H]⁻ 71 ¹H-NMR (DMSO-d₆) δ: 1.10-1.43 (m, 2H), 1.49-2.17(m, 7H), 2.36 (s, 3H), 2.87 (d, J = 6.6 Hz, 2H), 3.05-3.22 (m, 1H),6.73-6.90 (m, 1H), 7.40-7.59 (m, 1H), 9.50 (s, 1H), 12.50 (br s, 1H).LC/MS: condition 1, retention time = 3.88 min LC/MS (ESI⁺) m/z; 330 [M +H]⁺ LC/MS (ESI⁻) m/z; 328 [M − H]⁻ 72 ¹H-NMR (CDCl₃) δ: 1.17-1.40 (m,2H), 1.71-2.28 (m, 7H), 2.10 (s, 3H), 3.10-3.27 (m, 1H), 4.00 (d, J =6.6 Hz, 2H), 6.79 (dd, J = 3.3, 2.1 Hz, 1H), 7.21-7.35 (m, 1H), 9.12 (brs, 1H), 9.22 (s, 1H). LC/MS: condition 1, retention time = 3.55 minLC/MS (ESI⁺) m/z; 314 [M + H]⁺ LC/MS (ESI⁻) m/z; 312 [M − H]⁻ 73 ¹H-NMR(CDCl₃) δ: 1.20-1.50 (m, 2H), 1.64-2.40 (m, 7H), 3.05-3.60 (m, 1H),4.20-4.50 (m, 2H), 6.70-7.00 (m, 1H), 7.20-7.40 (m, 1H), 9.10 (br s,1H), 9.22 (s, 1H). LC/MS: condition 1, retention time = 3.63 min LC/MS(ESI⁺) m/z; 274 [M + H]⁺ LC/MS (ESI⁻) m/z; 272 [M − H]⁻ 74 ¹H-NMR(CDCl₃) δ: 1.20-1.45 (m, 2H), 1.75-2.28 (m, 7H), 3.07-3.23 (m, 1H), 3.41(d, J = 6.0 Hz, 2H), 6.72-6.84 (m, 1H), 7.24-7.35 (m, 1H), 9.02 (br s,1H), 9.22 (s, 1H). LC/MS: condition 1, retention time = 3.97 min LC/MS(ESI⁺) m/z; 334, 336 [M + H]⁺ LC/MS (ESI⁻) m/z; 332, 334 [M − H]⁻

TABLE^(a) 105 Ex Data 75 ¹H-NMR (CDCl₃) δ: 1.23-1.44 (m, 2H), 1.76-2.27(m, 7H), 3.09-3.25 (m, 1H), 3.51 (d, J = 6.6 Hz, 2H), 6.79 (dd, J = 3.3,2.1 Hz, 1H), 7.20-7.33 (m, 1H), 9.03 (br s, 1H), 9.22 (s, 1H). LC/MS:condition 2, retention time = 1.75 min LC/MS (ESI⁺) m/z; 290, 292 [M +H]⁺ 76 ¹H-NMR (CDCl₃) δ: 1.15-1.31 (m, 2H), 1.32-1.42 (m, 1H), 1.50-1.73(m, 1H), 1.85-2.03 (m, 2H), 2.04-2.25 (m, 4H), 2.55 (dd, J = 8.3, 6.6Hz, 2H), 3.06-3.25 (m, 1H), 6.72-6.85 (m, 1H), 7.20-7.36 (m, 1H), 9.00(br s, 1H), 9.21 (s, 1H). LC/MS: condition 1, retention time = 3.84 minLC/MS (ESI⁺) m/z; 288 [M + H]⁺ LC/MS (ESI⁻) m/z; 286 [M − H]⁻ 77 ¹H-NMR(CDCl₃) δ: 1.32-1.50 (m, 2H), 1.90-2.09 (m, 2H), 2.01-2.36 (m, 5H), 2.97(s, 3H), 3.04 (d, J = 5.4 Hz, 2H), 3.10-3.29 (m, 1H), 6.78 (dd, J = 2.1,3.3 Hz, 1H), 7.29 (t, J = 3.0 Hz, 1H), 9.00 (br s, 1H), 9.21 (s, 1H).LC/MS: condition 1, retention time = 2.87 min LC/MS (ESI⁺) m/z; 334 [M +H]⁺ LC/MS (ESI⁻) m/z; 332 [M − H]⁻ 78 ¹H-NMR (CDCl₃) δ: 1.41-1.69 (m,2H), 1.89-2.10 (m, 2H), 2.16-2.32 (m, 4H), 2.36-2.54 (m, 1H), 3.09-3.27(m, 1H), 6.70-6.80 (m, 1H), 7.27-7.35 (m, 1H), 9.03 (br s, 1H), 9.22 (s,1H), 9.74 (d, J = 1.2 Hz, 1H). LC/MS: condition 1, retention time = 3.13min LC/MS (ESI⁺) m/z; 270 [M + H]⁺ LC/MS (ESI⁻) m/z; 268 [M − H]⁻ 79¹H-NMR (CDCl₃) δ: 1.35-1.60 (m, 2H), 1.80-2.40 (m, 7H), 3.10-3.60 (m,1H), 5.40-5.90 (m, 1H), 6.72-6.85 (m, 1H), 7.20-7.40 (m, 1H), 9.02 (brs, 1H), 9.22 (s, 1H). LC/MS: condition 1, retention time = 3.74 minLC/MS (ESI⁺) m/z; 292 [M + H]⁺ LC/MS (ESI⁻) m/z; 290 [M − H]⁻ 80 ¹H-NMR(DMSO-d₆) δ: 1.60 (dq, J = 12.2, 2.3 Hz, 2H), 1.78 (dq, J = 12.6, 2.3Hz, 2H), 1.97-2.10 (m, 4H), 2.26-2.37 (m, 1H), 2.43-2.47 (m, 1H), 3.17(tt, J = 11.6, 3.3 Hz, 1H), 6.86 (d, J = 3.3 Hz, 1H), 7.49 (d, J = 3.0Hz, 1H), 9.52 (s, 1H), 12.53 (br s, 1H). LC/MS: condition 1, retentiontime = 2.70 min LC/MS (ESI⁺) m/z; 286 [M + H]⁺ LC/MS (ESI⁻) m/z; 284 [M− H]⁻ 81 ¹H-NMR (CD₃OD) δ: 1.54 (q, J = 11.2 Hz, 2H), 1.91 (dq, J =12.2, 4.0 Hz, 2H), 2.05-2.18 (m, 4H), 3.17 (dt, J = 12.9, 3.3 Hz, 1H),3.67-3.78 (m, 1H), 6.82 (d, J = 3.0 Hz, 1H), 7.40 (d, J = 3.3 Hz, 1H),9.30 (s, 1H). LC/MS: condition 1, retention time = 1.79 min LC/MS (ESI⁺)m/z; 258 [M + H]⁺ LC/MS (ESI⁻) m/z; 256 [M − H]⁻

TABLE^(a) 106 Ex Data 82 ¹H-NMR (CDCl₃) δ: 2.38-2.47 (m, 4H), 2.53-2.65(m, 2H), 2.71 (dt, J = 14.5, 5.0 Hz, 2H), 3.65-3.77 (m, 1H), 6.80 (dd, J= 3.6, 2.0 Hz, 1H), 7.33 (t, J = 3.0 Hz, 1H), 9.26 (s, 2H). LC/MS:condition 1, retention time = 2.55 min LC/MS (ESI⁺) m/z; 256 [M + H]⁺LC/MS (ESI⁻) m/z; 254 [M − H]⁻ 83 ¹H-NMR (CD₃OD) δ: 1.79 (m, 4H), 1.97(m, 2H), 2.34 (m, 2H), 3.26 (m, 1H), 4.10 (br s, 1H), 6.96 (d, J = 3.3Hz, 1H), 7.37 (d, J = 3.0 Hz, 1H), 7.89 (s, 1H), 9.28 (s, 1H). LC/MS:condition 1, retention time = 2.67 min LC/MS (ESI⁺) m/z; 258 [M + H]⁺LC/MS (ESI⁻) m/z; 256 [M − H]⁻ 84 ¹H-NMR (CDCl₃) δ: 1.97-2.09 (m, 4H),3.02 (br s, 2H), 3.19-3.26 (m, 1H), 4.37 (br s, 2H), 5.18 (s, 2H), 6.61(dd, J = 3.2, 2.3 Hz, 1H), 7.09 (t, J = 3.0 Hz, 1H), 7.28-7.41 (m, 5H),8.11 (s, 1H), 8.50 (s, 1H), 8.89 (br s, 1H). LC/MS: condition 3,retention time = 2.05 min LC/MS (ESI⁺) m/z; 376 [M + H]⁺ 85 ¹H-NMR(DMSO-d₆) δ: 1.64-1.92 (m, 4H), 3.01 (br s, 2H), 3.20-3.30 (m, 1H),4.07-4.20 (m, 2H), 5.12 (s, 2H), 6.63 (br s, 1H), 7.14-7.20 (m, 1H),7.29-7.43 (m, 5H), 8.63 (s, 1H), 12.05 (br s, 1H), 13.14 (br s, 1H).LC/MS: condition 3, retention time = 2.20 min LC/MS (ESI⁺) m/z; 408 [M +H]⁺ LC/MS (ESI⁻) m/z; 406 [M − H]⁻ 86 ¹H-NMR (DMSO-d₆) δ: 1.62-1.76 (m,2H), 1.90-2.09 (m, 2H), 2.13-2.28 (m, 2H), 2.85-3.05 (m, 3H), 3.63 (s,2H), 6.56 (br s, 1H), 7.14-7.21 (m, 1H), 7.69 (d, J = 8.3 Hz, 2H), 7.71(d, J = 8.3 Hz, 2H), 8.64 (s, 1H), 12.05 (br s, 1H), 13.14 (br s, 1H).LC/MS: condition 3, retention time = 1.64 min LC/MS (ESI⁺) m/z; 432 [M +H]⁺ LC/MS (ESI⁻) m/z; 430 [M − H]⁻ 87 LC/MS: condition 3, retention time= 2.01 min LC/MS (ESI⁺) m/z; 349 [M + H]⁺ LC/MS (ESI⁻) m/z; 347 [M − H]⁻88 ¹H-NMR (CDCl₃) δ: 1.07-1.33 (m, 2H), 1.45-1.73 (m, 1H), 1.80-2.28 (m,6H), 2.40 (d, J = 7.1 Hz, 2H), 2.90-3.28 (m, 9H), 6.71-6.84 (m, 1H),7.20-7.40 (m, 1H), 9.02 (br s, 1H), 9.22 (s, 1H). LC/MS: condition 1,retention time = 1.84 min LC/MS (ESI⁺) m/z; 389 [M + H]⁺ LC/MS (ESI⁻)m/z; 387 [M − H]⁻ 89 ¹H-NMR (CDCl₃) δ: 1.04-1.24 (m, 2H), 1.60-2.40 (m,15H), 2.55-2.77 (m, 3H), 3.05-3.25 (m, 1H), 6.71-6.84 (m, 1H), 7.20-7.36(m, 1H), 8.99 (br s, 1H), 9.21 (s, 1H). LC/MS: condition 1, retentiontime = 0.39 min LC/MS (ESI⁺) m/z; 364 [M + H]⁺ LC/MS (ESI⁻) m/z; 362 [M− H]⁻

TABLE^(a) 107 Ex Data 90 ¹H-NMR (CDCl₃) δ: 1.21-1.32 (m, 2H), 1.40-2.27(m, 8H), 2.50-2.75 (m, 4H), 2.97 (t, J = 6.3 Hz, 2H), 3.10-3.25 (m, 1H),6.71-6.87 (m, 1H), 7.20-7.35 (m, 1H), 9.00 (br s, 1H), 9.21 (s, 1H).LC/MS: condition 1, retention time = 0.37 min LC/MS (ESI⁺) m/z; 324 [M +H]⁺ LC/MS (ESI⁻) m/z; 322 [M − H]⁻ 91 ¹H-NMR (CDCl₃) δ: 1.05-1.31 (m,2H), 1.61-1.80 (m, 1H), 1.81-1.99 (m, 2H), 2.00-2.20 (m, 4H), 2.24 (d, J= 7.1 Hz, 2H), 2.39-2.53 (m, 4H), 3.10-3.25 (m, 1H), 3.65-3.81 (m, 4H),6.71-6.85 (m, 1H), 7.20-7.35 (m, 1H), 9.00 (br s, 1H), 9.21 (s, 1H).LC/MS: condition 1, retention time = 0.37 min LC/MS (ESI⁺) m/z; 341 [M +H]⁺ LC/MS (ESI⁻) m/z; 339 [M − H]⁻ 92 ¹H-NMR (DMSO-d₆) δ: 1.15-1.40 (m,2H), 1.55-1.90 (m, 3H), 1.92-2.12 (m, 4H), 2.99-3.09 (m, 2H), 3.00-3.26(m, 1H), 6.69 (d, J = 8.9 Hz, 2H), 6.81 (d, J = 3.3 Hz, 2H), 7.45 (d, J= 8.6 Hz, 2H), 7.50 (d, J = 3.3 Hz, 1H), 9.52 (s, 1H), 12.54 (br s, 1H).LC/MS: condition 1, retention time = 3.95 min LC/MS (ESI⁺) m/z; 372 [M +H]⁺ LC/MS (ESI⁻) m/z; 370 [M − H]⁻ 93 ¹H-NMR (CDCl₃) δ: 1.10-1.31 (m,2H), 1.50-1.77 (m, 1H), 1.82-2.20 (m, 6H), 2.56 (d, J = 6.6 Hz, 2H),3.07-3.23 (m, 1H), 3.89 (s, 2H), 6.78 (dd, J = 3.3, 2.1 Hz, 1H),7.21-7.32 (m, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.56-7.68 (m, 2H), 9.02 (brs, 1H), 9.21 (s, 1H). LC/MS: condition 1, retention time = 2.27 minLC/MS (ESI⁺) m/z; 386 [M + H]⁺ LC/MS (ESI⁻) m/z; 384 [M − H]⁻ 94 ¹H-NMR(CDCl₃) δ: 1.10-1.30 (m, 2H), 1.50-1.75 (m, 1H), 1.82-2.30 (m, 8H),2.33-2.60 (m, 3H), 2.63-2.97 (m, 3H), 3.05-3.40 (m, 1H), 5.02-5.33 (m,1H), 6.72-6.84 (m, 1H), 7.20-7.34 (m, 1H), 9.15 (br s, 1H), 9.21 (s,1H). LC/MS: condition 1, retention time = 0.44 min LC/MS (ESI⁺) m/z; 343[M + H]⁺ LC/MS (ESI⁻) m/z; 341 [M − H]⁻ 95 ¹H-NMR (CDCl₃) δ: 1.04-1.32(m, 2H), 1.50-1.77 (m, 1H), 1.81-2.29 (m, 8H), 2.33-2.61 (m, 3H),2.65-2.98 (m, 3H), 3.09-3.40 (m, 1H), 5.00-5.35 (m, 1H), 6.73-6.85 (m,1H), 7.21-7.35 (m, 1H), 9.12 (br s, 1H), 9.21 (s, 1H). LC/MS: condition1, retention time = 0.42 min LC/MS (ESI⁺) m/z; 343 [M + H]⁺ LC/MS (ESI⁻)m/z; 341 [M − H]⁻ 96 ¹H-NMR (CDCl₃) δ: 1.05-1.21 (m, 2H), 1.23 (s, 6H),1.48-1.66 (m, 1H), 1.79-2.17 (m, 8H), 2.43 (d, J = 6.8 Hz, 2H),3.00-3.23 (m, 1H), 3.05 (s, 2H), 6.72-6.82 (m, 1H), 7.20-7.32 (m, 1H),9.21 (s, 1H), 9.41 (br s, 1H). LC/MS: condition 1, retention time = 0.79min LC/MS (ESI⁺) m/z; 339 [M + H]⁺ LC/MS (ESI⁻) m/z; 337 [M − H]⁻

TABLE^(a) 108 Ex Data 97 ¹H-NMR (CDCl₃) δ: 1.05-1.33 (m, 2H), 1.50-1.80(m, 1H), 1.82-2.20 (m, 10H), 2.28 (d, J = 7.4 Hz, 2H), 2.49-2.62 (m,4H), 3.07-3.44 (m, 1H), 6.79 (dd, J = 3.3, 2.1 Hz, 1H), 7.20-7.34 (m,1H), 9.15 (br s, 1H), 9.22 (s, 1H). LC/MS: condition 1, retention time =0.62 min LC/MS (ESI⁺) m/z; 375 [M + H]⁺ LC/MS (ESI⁻) m/z; 373 [M − H]⁻98 ¹H-NMR (DMSO-d₆) δ: 1.06-1.30 (m, 2H), 1.50-1.66 (m, 1H), 1.68-1.85(m, 2H), 1.90-2.08 (m, 4H), 2.42 (d, J = 6.6 Hz, 1H), 3.03-3.20 (m, 1H),3.25-3.38 (m, 1H), 3.81 (s, 2H), 6.70-6.85 (m, 1H), 7.40-7.51 (m, 1H),7.58 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 9.51 (s, 1H), 12.51(br s, 1H). LC/MS: condition 1, retention time = 2.95 min LC/MS (ESI⁺)m/z; 429 [M + H]⁺ LC/MS (ESI⁻) m/z; 427 [M − H]⁻ 99 ¹H-NMR (DMSO-d₆) δ:1.19-1.40 (m, 2H), 1.65-1.88 (m, 3H), 1.95-2.11 (m, 4H), 2.95-3.07 (m,2H), 3.10-3.25 (m, 1H), 6.40-6.52 (m, 1H), 6.69 (d, J = 8.6 Hz, 2H),6.76-6.87 (m, 1H), 7.36 (d, J = 8.6 Hz, 2H), 7.45-7.55 (m, 1H), 9.51 (s,1H), 12.52 (br s, 1H). LC/MS: condition 1, retention time = 4.49 minLC/MS (ESI⁺) m/z; 415 [M + H]⁺ LC/MS (ESI⁻) m/z; 413 [M − H]⁻ 100 ¹H-NMR(DMSO-d₆) δ: 1.16-1.40 (m, 2H), 1.61-1.88 (m, 3H), 1.94-2.10 (m, 4H),2.85-3.00 (m, 2H), 3.10-3.25 (m, 1H), 5.52-5.65 (m, 1H), 6.50-6.63 (m,2H), 6.76-6.82 (m, 1H), 6.85-6.98 (m, 2H), 7.49 (t, J = 3.0, 1H), 9.51(s, 1H), 12.52 (br s, 1H). LC/MS: condition 1, retention time = 3.63 minLC/MS (ESI⁺) m/z; 365 [M + H]⁺ 101 ¹H-NMR (DMSO-d₆) δ: 1.10-1.30 (m,2H), 1.50-2.10 (m, 9H), 3.08-3.21 (m, 1H), 3.69-3.90 (m, 2H), 6.79 (d, J= 3.3 Hz, 1H), 7.10-7.25 (m, 2H), 7.38-7.56 (m, 3H), 9.51 (s, 1H), 12.52(br s, 1H). LC/MS: condition 1, retention time = 2.67 min LC/MS (ESI⁺)m/z; 379 [M + H]⁺ LC/MS (ESI⁻) m/z; 377 [M − H]⁻ 102 ¹H-NMR (DMSO-d₆) δ:1.18-1.40 (m, 2H), 1.60-2.10 (m, 7H), 2.92 (s, 3H), 3.05-3.25 (m, 3H),6.68 (dd, J = 9.5, 4.2 Hz, 2H), 6.76-6.83 (m, 1H), 6.94-7.08 (m, 2H),7.41-7.54 (m, 1H), 9.50 (s, 1H), 12.52 (br s, 1H). LC/MS: condition 1,retention time = 3.80 min LC/MS (ESI⁺) m/z; 379 [M + H]⁺ LC/MS (ESI⁻)m/z; 377 [M − H]⁻ 103 ¹H-NMR (DMSO-d₆) δ: 1.15-1.37 (m, 2H), 1.65-1.88(m, 3H), 1.91-2.08 (m, 4H), 2.12 (s, 3H), 3.05-3.23 (m, 3H), 5.89-6.00(m, 1H), 6.65 (d, J = 8.6 Hz, 1H), 6.75-6.84 (m, 1H), 7.26-7.53 (m, 3H),9.51 (s, 1H), 12.51 (br s, 1H). LC/MS: condition 1, retention time =4.07 min LC/MS (ESI⁺) m/z; 386 [M + H]⁺ LC/MS (ESI⁻) m/z; 384 [M − H]⁻

TABLE^(a) 109 Ex Data 104 ¹H-NMR (DMSO-d₆) δ: 1.15-1.38 (m, 2H),1.66-1.90 (m, 3H), 1.95-2.10 (m, 4H), 2.13 (s, 3H), 2.95-3.08 (m, 2H),3.10-3.25 (m, 1H), 6.56 (d, J = 8.3 Hz, 1H), 6.76-6.85 (m, 1H),6.91-7.05 (m, 2H), 7.41-7.54 (m, 1H), 9.51 (s, 1H), 12.51 (br s, 1H).LC/MS: condition 1, retention time = 4.67 min LC/MS (ESI⁺) m/z; 445 [M +H]⁺ LC/MS (ESI⁻) m/z; 443 [M − H]⁻ 105 ¹H-NMR (DMSO-d₆) δ: 1.15-1.40 (m,2H), 1.65-1.88 (m, 3H), 1.95-2.10 (m, 4H), 3.01-3.25 (m, 3H), 6.75-6.95(m, 2H), 7.01-7.12 (m, 1H), 7.27-7.39 (m, 1H), 7.43-7.53 (m, 1H),7.66-7.77 (m, 1H), 9.51 (s, 1H), 12.52 (br s, 1H). LC/MS: condition 1,retention time = 4.22 min LC/MS (ESI⁺) m/z; 440 [M + H]⁺ LC/MS (ESI⁻)m/z; 438 [M − H]⁻ 106 ¹H-NMR (DMSO-d₆) δ: 1.06-1.29 (m, 2H), 1.45-1.63(m, 1H), 1.65-1.85 (m, 2H), 1.89-2.07 (m, 4H), 2.32-2.62 (m, 2H), 2.39(s, 3H), 3.05-3.20 (m, 1H), 3.74-3.89 (m, 2H), 6.55-6.67 (m, 1H), 6.71(d J = 3.3 Hz, 1H), 6.80 (d, J = 2.7 Hz, 1H), 7.42-7.54 (m, 1H), 9.50(s, 1H), 12.51 (br s, 1H). LC/MS: condition 1, retention time = 2.75 minLC/MS (ESI⁺) m/z; 381 [M + H]⁺ LC/MS (ESI⁻) m/z; 379 [M − H]⁻ 107 ¹H-NMR(DMSO-d₆) δ: 1.06-1.30 (m, 2H), 1.45-1.63 (m, 1H), 1.65-1.87 (m, 2H),1.89-2.08 (m, 4H), 2.77 (t, J = 5.4 Hz, 1H), 2.81-2.91 (m, 1H),3.05-3.20 (m, 1H), 4.39 (t, J = 5.1 Hz, 1H), 4.49-4.61 (m, 1H),6.72-6.85 (m, 1H), 7.40-7.53 (m, 1H), 9.51 (s, 1H), 12.51 (br s, 1H).LC/MS: condition 1, retention time = 0.39 min LC/MS (ESI⁺) m/z; 317 [M +H]⁺ LC/MS (ESI⁻) m/z; 315 [M − H]⁻ 108 ¹H-NMR (DMSO-d₆) δ: 1.19-1.42 (m,2H), 1.60-2.10 (m, 7H), 3.05 (s, 3H), 3.07-3.22 (m, 1H), 3.25-3.41 (m,2H), 6.70-6.90 (m, 3H), 7.40-7.60 (m, 3H), 9.50 (s, 1H), 12.51 (br s,1H). LC/MS: condition 1, retention time = 4.10 min LC/MS (ESI⁺) m/z; 386[M + H]⁺ LC/MS (ESI⁻) m/z; 384 [M − H]⁻ 109 ¹H-NMR (CDCl₃) δ: 1.12-1.28(m, 2H), 1.33 (d, J = 6.6 Hz, 3H), 1.37-2.16 (m, 7H), 2.30 (dd, J =11.4, 6.9 Hz, 1H), 2.48 (dd, J = 11.7, 6.3 Hz, 1H), 3.15 (tt, J = 12.0,3.3 Hz, 1H), 3.74 (q, J = 6.3 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H),7.05-7.7.28 (m, 4H), 9.23 (s, 1H), 9.52 (br s, 1H). LC/MS: condition 1,retention time = 2.89 min LC/MS (ESI⁺) m/z; 411 [M + H]⁺ LC/MS (ESI⁻)m/z; 409 [M − H]⁻

TABLE^(a) 110 Ex Data 110 ¹H-NMR (CDCl₃) δ: 1.22 (m, 2H), 1.86-2.17 (m,7H), 2.58 (d, J = 6.6 Hz, 2H), 3.18 (tt, J = 11.7, 3.6 Hz, 1H), 3.83 (s,2H), 6.77 (m, 1H), 7.16-7.39 (m, 5H), 9.22 (s, 1H), 9.43 (br s, 1H).LC/MS: condition 1, retention time = 3.03 min LC/MS (ESI⁺) m/z; 445 [M +H]⁺ LC/MS (ESI⁻) m/z; 443 [M − H]⁻ 111 ¹H-NMR (CDCl₃) δ: 1.22 (m, 2H),1.85-2.14 (m, 7H), 2.58 (d, J = 6.6 Hz, 2H), 2.72-2.95 (m, 4H), 3.16(tt, J = 11.7, 3.3 Hz, 1H), 6.78 (d, J = 3.9 Hz, 1H), 6.95-7.27 (m, 5H),9.21 (s, 1H). LC/MS: condition 1, retention time = 2.81 min LC/MS (ESI⁺)m/z; 393 [M + H]⁺ LC/MS (ESI⁻) m/z; 391 [M − H]⁻ 112 ¹H-NMR (CDCl₃) δ:1.25 (m, 2H), 1.70 (m, 1H), 1.86-2.18 (m, 6H), 2.57 (d, J = 6.6 Hz, 2H),3.17 (tt, J = 11.7, 3.6 Hz, 1H), 3.84 (s, 2H), 6.78 (m, 1H), 7.15 (t, J= 9.9 Hz, 1H), 7.29 (t, J = 2.7 Hz, 1H), 7.54 (m, 1H), 7.60 (dd, J =6.9, 1.5 Hz, 1H), 9.25 (s, 1H), 9.60 (br s, 1H). LC/MS: condition 1,retention time = 2.97 min LC/MS (ESI⁺) m/z; 447 [M + H]⁺ LC/MS (ESI⁻)m/z; 445 [M − H]⁻ 113 ¹H-NMR (CDCl₃) δ: 1.22 (m, 2H), 1.87-2.17 (m, 7H),2.57 (d, J = 6.6 Hz, 2H), 3.06 (s, 3H), 3.16 (tt, J = 12.0, 3.3 Hz, 1H),3.93 (s, 2H), 6.78 (m, 1H), 7.27, (m, 1H), 7.58 (d, J = 8.4 Hz, 2H),7.90 (d, J = 8.7 Hz, 2H), 9.09 (br s, 1H), 9.21 (s, 1H). LC/MS:condition 1, retention time = 0.70 min LC/MS (ESI⁺) m/z; 439 [M + H]⁺114 ¹H-NMR (DMSO-d₆) δ: 1.27 (q, J = 11.4 Hz, 2H), 1.68-1.85 (m, 3H),1.96-2.09 (m, 4H), 2.94 (t, J = 5.7 Hz, 1H), 3.17 (d, J = 5.3 Hz, 2H),5.96 (t, J = 5.7 Hz, 1H), 6.62 (d, J = 9.0 Hz, 2H), 6.80 (dd, J = 3.3,1.2 Hz, 1H), 7.04 (d, J = 8.6 Hz, 2H), 7.48 (t, J = 2.5 Hz, 1H), 9.51(s, 1H), 12.51 (br s, 1H). LC/MS: condition 1, retention time = 4.49 minLC/MS (ESI⁺) m/z; 431 [M + H]⁺ LC/MS (ESI⁻) m/z; 429 [M − H]⁻ 115 ¹H-NMR(DMSO-d₆) δ: 1.26 (q, J = 11.4 Hz, 2H), 1.76 (q, J = 12.3 Hz, 3H),1.92-2.07 (m, 4H), 3.10 (t, J = 6.1 Hz, 2H), 5.61 (t, J = 6.1 Hz, 1H),6.78-6.82 (m, 2H), 7.17 (dd, J = 8.6, 2.5 Hz, 1H), 7.35 (dd, J = 2.9,0.8 Hz, 1H), 7.48 (t, J = 2.9 Hz, 1H), 9.51 (s, 1H), 12.51 (br s, 1H).LC/MS: condition 1, retention time = 4.77 min LC/MS (ESI⁺) m/z; 465 [M +H]⁺ LC/MS (ESI⁻) m/z; 463 [M − H]⁻

TABLE^(a) 111 Ex Data 116 ¹H-NMR (DMSO-d₆) δ: 1.25 (q, J = 11.4 Hz, 2H),1.67-1.83 (m, 3H), 1.91-2.07 (m, 4H), 3.08-3.22 (m, 3H), 6.08 (t, J =5.7 Hz, 1H), 6.79-6.87 (m, 2H), 7.33 (td, J = 9.0, 3.3 Hz, 1H), 7.42(dd, J = 8.6, 2.9 Hz, 1H), 7.48 (d, J = 2.9 Hz, 1H), 9.51 (s, 1H), 12.51(br s, 1H). LC/MS: condition 1, retention time = 4.15 min LC/MS (ESI⁺)m/z; 390 [M + H]⁺ LC/MS (ESI⁻) m/z; 388 [M − H]⁻ 117 ¹H-NMR (DMSO-d₆) δ:1.25 (dq, J = 12.3, 2.5 Hz, 2H), 1.67-1.83 (m, 3H), 1.94-2.03 (m, 4H),3.07-3.22 (m, 3H), 5.33 (t, J = 5.7 Hz, 1H), 6.80 (d, J = 2.9 Hz, 1H),6.88 (dd, J = 9.0, 4.5 Hz, 1H), 7.28 (dd, J = 9.0, 3.3 Hz, 1H), 7.33(dd, J = 9.0, 3.3 Hz, 1H), 7.48 (br s, 1H), 9.50 (s, 1H), 12.51 (br s,1H). LC/MS: condition 1, retention time = 4.55 min LC/MS (ESI⁺) m/z; 433[M + H]⁺ LC/MS (ESI⁻) m/z; 431 [M − H]⁻ 118 ¹H-NMR (DMSO-d₆) δ: 1.26 (q,J = 11.9 Hz, 2H), 1.67-1.84 (m, 3H), 1.96-2.08 (m, 4H), 2.90 (br s, 5H),3.17 (t, J = 12.3 Hz, 1H), 3.31 (s, 2H), 3.71 (t, J = 3.7 Hz, 4H), 6.55(d, J = 7.8 Hz, 2H), 6.77 (d, J = 7.8 Hz, 2H), 6.80 (dd, J = 3.3, 2.0Hz, 1H), 7.48 (t, J = 2.9 Hz, 1H), 9.51 (s, 1H), 12.52 (br s, 1H).LC/MS: condition 1, retention time = 2.80 min LC/MS (ESI⁺) m/z; 432 [M +H]⁺ LC/MS (ESI⁻) m/z; 430 [M − H]⁻ 119 ¹H-NMR (CDCl₃) δ: 1.06-1.37 (m,2H), 1.57-2.37 (m, 11H), 2.38-2.47 (m, 2H), 2.48-2.59 (m, 1H), 2.72-2.87(m, 1H), 2.90-3.04 (m, 1H), 3.09-3.25 (m, 1H), 4.25-4.44 (m, 1H),6.71-6.87 (m, 1H), 7.22-7.38 (m, 1H), 9.10 (br s, 1H), 9.21 (s, 1H).LC/MS: condition 1, retention time = 0.39 min LC/MS (ESI⁺) m/z; 341 [M +H]⁺ LC/MS (ESI⁻) m/z; 339 [M − H]⁻ 120 ¹H-NMR (CDCl₃) δ: 1.11-1.33 (m,2H), 1.42-1.81 (m, 2H), 1.83-2.23 (m, 10H), 2.51-2.83 (m, 4H), 3.07-3.25(m, 1H), 3.70-3.94 (m, 2H), 3.99-4.14 (m, 1H), 6.72-6.83 (m, 1H),7.21-7.35 (m, 1H), 9.05 (br s, 1H), 9.21 (s, 1H). LC/MS: condition 1,retention time = 1.19 min LC/MS (ESI⁺) m/z; 355 [M + H]⁺ LC/MS (ESI⁻)m/z; 353 [M − H]⁻ 121 LC/MS: condition 1, retention time = 3.74, 3.87min (cis/trans mixture) LC/MS (ESI⁺) m/z; 358 [M + H]⁺ LC/MS (ESI⁻) m/z;356 [M − H]⁻ 122 LC/MS: condition 1, retention time = 0.36 min(cis/trans mixture) LC/MS (ESI⁺) m/z; 362 [M + H]⁺ LC/MS (ESI⁻) m/z; 360[M − H]⁻ 123 LC/MS: condition 1, retention time = 2.61 min (cis/transmixture) LC/MS (ESI⁺) m/z; 361 [M + H]⁺ LC/MS (ESI⁻) m/z; 359 [M − H]⁻

TABLE^(a) 112 Ex Data 124 LC/MS: condition 1, retention time = 0.39 min(cis/trans mixture) LC/MS (ESI⁺) m/z; 327 [M + H]⁺ LC/MS (ESI⁻) m/z; 325[M − H]⁻ 125 LC/MS: condition 1, retention time = 3.04 min (cis/transmixture) LC/MS (ESI⁺) m/z; 429 [M + H]⁺ LC/MS (ESI⁻) m/z; 427 [M − H]⁻126 LC/MS: condition 1, retention time = 0.36 min (cis/trans mixture)LC/MS (ESI⁺) m/z; 370 [M + H]⁺ LC/MS (ESI⁻) m/z; 368 [M − H]⁻ 127 LC/MS:condition 1, retention time = 0.37 min (cis/trans mixture) LC/MS (ESI⁺)m/z; 350 [M + H]⁺ LC/MS (ESI⁻) m/z; 348 [M − H]⁻ 128 LC/MS: condition 1,retention time = 4.25, 4.39 min (cis/trans mixture) LC/MS (ESI⁺) m/z;401 [M + H]⁺ LC/MS (ESI⁻) m/z; 399 [M − H]⁻ 129 LC/MS: condition 1,retention time = 3.95 min (cis/trans mixture) LC/MS (ESI⁺) m/z; 376 [M +H]⁺ LC/MS (ESI⁻) m/z; 374 [M − H]⁻ 130 LC/MS: condition 1, retentiontime = 2.79 min (cis/trans mixture) LC/MS (ESI⁺) m/z; 365 [M + H]⁺ LC/MS(ESI⁻) m/z; 363 [M − H]⁻ 131 LC/MS: condition 1, retention time = 2.84,3.24 min (cis/trans mixture) LC/MS (ESI⁺) m/z; 351 [M + H]⁺ LC/MS (ESI⁻)m/z; 349 [M − H]⁻ 132 LC/MS: condition 1, retention time = 3.94, 4.02min (cis/trans mixture) LC/MS (ESI⁺) m/z; 372 [M + H]⁺ LC/MS (ESI⁻) m/z;370 [M − H]⁻ 133 LC/MS: condition 1, retention time = 4.45 min(cis/trans mixture) LC/MS (ESI⁺) m/z; 431 [M + H]⁺ LC/MS (ESI⁻) m/z; 429[M − H]⁻ 134a ¹H-NMR (DMSO-d₆) δ: 1.82-1.95 (m, 6H), 2.07-2.23 (m, 2H),3.35-3.43 (m, 1H), 3.67 (br s, 1H), 6.77-6.73 (m, 3H), 6.86 (dd, J =2.9, 1.2 Hz, 1H), 7.44 (d, J = 9.0 Hz, 2H), 7.50 (t, J = 2.9 Hz, 1H),9.53 (s, 1H), 12.53 (br s, 1H). LC/MS: condition 1, retention time =3.88 min LC/MS (ESI⁺) m/z; 358 [M + H]⁺ LC/MS (ESI⁻) m/z; 356 [M − H]⁻134b ¹H-NMR (DMSO-d₆) δ: 1.48 (dq, J = 11.9, 3.7 Hz, 2H), 1.86-2.18 (m,6H), 3.15-3.25 (m, 1H), 3.50 (br s, 1H), 6.64 (d, J = 8.1, 1H), 6.72 (d,J = 8.6 Hz, 2H), 6.90 (dd, J = 3.3, 1.6 Hz, 1H), 7.44 (d, J = 8.6 Hz,2H), 7.50 (t, J = 2.9 Hz, 1H), 9.52 (s, 1H), 12.53 (br s, 1H). LC/MS:condition 1, retention time = 3.74 min LC/MS (ESI⁺) m/z; 358 [M + H]⁺LC/MS (ESI⁻) m/z; 356 [M − H]⁻

TABLE^(a) 113 Ex Data 135a ¹H-NMR (CDCl₃) δ: 1.91 (m, 6H), 2.29 (m, 2H),2.92 (m, 5H), 3.34 (tt, J = 9.9, 3.6 Hz, 1H), 7.10 (d, J = 3.3 Hz, 1H),7.18-7.33 (m, 6H), 9.21 (s, 1H), 9.69 (br s, 1H). LC/MS: condition 1,retention time = 2.78 min LC/MS (ESI⁺) m/z; 361 [M + H]⁺ LC/MS (ESI⁻)m/z; 359 [M − H]⁻ 135b ¹H-NMR (CDCl₃) δ: 1.30 (m, 2H), 1.88 (m, 2H),2.07 (m, 4H), 2.62 (tt, J = 11.4, 3.3 Hz, 1H), 2.79 (t, J = 7.5 Hz, 2H),2.95 (t, J = 7.2 Hz, 2H), 3.10 (tt, J = 12.3, 3.3 Hz, 1H), 6.68 (d, J =2.7 Hz, 1H), 7.12-7.26 (m, 6H), 9.15 (s, 1H), 9.95 (br s, 1H). LC/MS:condition 1, retention time = 2.51 min LC/MS (ESI⁺) m/z; 361 [M + H]⁺LC/MS (ESI⁻) m/z; 359 [M − H]⁻ 136a ¹H-NMR (CDCl₃) δ: 1.31-1.94 (m,10H), 2.30 (m, 1H), 2.72 (m, 4H), 2.92 (s, 1H), 3.30 (m, 1H), 7.14-7.34(m, 7H), 9.21 (s, 1H), 9.48 (br s, 1H). LC/MS: condition 1, retentiontime = 2.84 min LC/MS (ESI⁺) m/z; 375 [M + H]⁺ LC/MS (ESI⁻) m/z; 373 [M− H]⁻ 136b ¹H-NMR (CDCl₃) δ: 1.37 (m, 2H), 1.80-2.01 (m, 5H), 2.13 (m,4H), 2.63 (m, 1H), 2.70 (t, J = 7.5 Hz, 1H), 2.76 (t, J = 7.5 Hz, 1H),3.26 (m, 1H), 3.17 (m, 1H), 6.76 (d, J = 3.6 Hz, 1H), 7.16-7.34 (m, 6H),9.21 (br s, 1H), 9.21 (s, 1H). LC/MS: condition 1, retention time = 2.76min LC/MS (ESI⁺) m/z; 375 [M + H]⁺ LC/MS (ESI⁻) m/z; 373 [M − H]⁻ 136b¹H-NMR (CDCl₃) δ: 1.37 (m, 2H), 1.80-2.01 (m, 5H), 2.13 (m, 4H), 2.63(m, 1H), 2.70 (t, J = 7.5 Hz, 1H), 2.76 (t, J = 7.5 Hz, 1H), 3.26 (m,1H), 3.17 (m, 1H), 6.76 (d, J = 3.6 Hz, 1H), 7.16-7.34 (m, 6H), 9.21 (brs, 1H), 9.21 (s, 1H). LC/MS: condition 1, retention time = 2.76 minLC/MS (ESI⁺) m/z; 375 [M + H]⁺ LC/MS (ESI⁻) m/z; 373 [M − H]⁻ 137a¹H-NMR (DMSO-d₆) δ: 1.56-1.71 (m, 4H), 1.80-1.90 (m, 2H), 2.19-2.35 (m,2H), 2.84 (br s, 1H), 3.19-3.26 (m, 1H), 3.84 (br s, 2H), 7.08 (d, J =3.0 Hz, 1H), 7.43 (t, J = 2.6 Hz, 1H), 7.63 (d, J = 8.3 Hz, 2H), 7.83(d, J = 8.3 Hz, 2H), 9.52 (s, 1H), 12.51 (br s, 1H). LC/MS: condition 1,retention time = 1.03 min LC/MS (ESI⁺) m/z; 372 [M + H]⁺ 137b ¹H-NMR(CDCl₃) δ: 1.40 (dq, J = 12.6, 3.3 Hz, 2H), 1.96 (dq, J = 12.9, 4.0 Hz,2H), 2.12-2.22 (m, 4H), 2.71 (tt, J = 11.2, 3.6 Hz, 1H), 3.19 (tt, J =12.2, 3.3 Hz, 1H), 3.96 (s, 2H), 6.77 (dd, J = 3.6, 2.3 Hz, 1H), 7.30(t, J = 3.0 Hz, 1H), 7.50 (d, J = 7.9 Hz, 2H), 7.64 (d, J = 8.3 Hz, 2H),9.14 (br s, 1H), 9.23 (s, 1H). LC/MS: condition 1, retention time = 0.85min LC/MS (ESI⁺) m/z; 372 [M + H]⁺ LC/MS (ESI⁻) m/z; 370 [M − H]⁻

TABLE^(a) 114 Ex Data 138a ¹H-NMR (CDCl₃) δ: 1.74 (t, J = 3.3 Hz, 1H),1.76-1.87 (m, 4H), 1.95 (br s, 2H), 2.27-2.42 (m, 2H), 2.99-3.05 (m,1H), 3.29-3.41 (m, 1H), 3.91 (s, 2H), 7.10 (dd, J = 3.3, 2.0 Hz, 1H),7.19 (t, J = 2.6 Hz, 1H), 7.53 (d, J = 8.3 Hz, 2H), 7.61 (d, J = 8.3 Hz,2H), 9.23 (s, 1H), 9.31 (br s, 1H). LC/MS: condition 1, retention time =2.87 min LC/MS (ESI⁺) m/z; 415 [M + H]⁺ LC/MS (ESI⁻) m/z; 413 [M − H]⁻138b ¹H-NMR (DMSO-d₆) δ: 1.35 (q, J = 10.6 Hz, 2H), 1.76 (q, J = 12.2Hz, 2H), 1.95-2.14 (m, 4H), 2.19-2.32 (m, 1H), 3.15 (t, J = 12.2 Hz,1H), 3.89 (s, 2H), 6.80 (d, J = 2.6 Hz, 1H), 7.49 (br s, 1H), 7.61 (d, J= 8.6 Hz, 2H), 7.69 (d, J = 8.3 Hz, 2H), 9.52 (d, J = 1.3 Hz, 1H), 12.53(br s, 1H). LC/MS: condition 1, retention time = 2.72 min LC/MS (ESI⁺)m/z; 415 [M + H]⁺ LC/MS (ESI⁻) m/z; 413 [M − H]⁻ 139a ¹H-NMR (CDCl₃) δ:1.64-1.78 (m, 5H), 1.90-1.99 (m, 2H), 2.33 (dq, J = 13.2, 3.0 Hz, 2H),2.74 (br s, 4H), 3.21 (t, J = 3.3 Hz, 1H), 3.27-3.38 (m, 1H), 3.75 (t, J= 4.6 Hz, 4H), 7.23 (dd, J = 3.6, 2.0 Hz, 1H), 7.28 (t, J = 3.0 Hz, 1H),9.21 (br s, 1H), 9.22 (s, 1H). LC/MS: condition 1, retention time = 0.79min LC/MS (ESI⁺) m/z; 342 [M + H]⁺ 139b ¹H-NMR (CDCl₃) δ: 1.37 (dq, J =12.9, 4.0 Hz, 2H), 1.57 (br s, 1H), 1.96 (dq, J = 12.6, 3.0 Hz, 2H),2.08-2.19 (m, 4H), 2.69 (br s, 4H), 2.94 (tt, J = 11.2, 3.3 Hz, 1H),3.18 (tt, J = 12.2, 4.0 Hz, 1H), 3.76 (t, J = 4.6 Hz, 4H), 6.78 (dd, J =3.3, 2.3 Hz, 1H), 7.29 (t, J = 2.6 Hz, 1H), 9.09 (br s, 1H), 9.22 (s,1H). LC/MS: condition 1, retention time = 0.57 min LC/MS (ESI⁺) m/z; 342[M + H]⁺ 140  ¹H-NMR (DMSO-d₆) δ: 4.59 (d, J = 5.4 Hz, 2H), 5.27 (t, J =6.0 Hz, 1H), 6.86 (m, 1H), 7.54 (m, 3H), 7.92 (d, J = 8.1 Hz, 2H), 9.65(s, 1H), 12.68 (br s, 1H). LC/MS: condition 1, retention time = 2.77 minLC/MS (ESI⁺) m/z; 266 [M + H]⁺ LC/MS (ESI⁻) m/z; 264 [M − H]⁻ 141 ¹H-NMR (DMSO-d₆) δ: 1.25 (m, 2H), 1.66 (m, 1H), 1.87 (m, 2H), 2.00-2.15(m, 4H), 3.18 (tt, J = 12.3 Hz, 3.6 Hz, 1H), 3.47 (d, J = 6.6 Hz, 2H),6.81 Hz (d, J = 3.3 Hz, 1H), 7.38 (d, J = 3.3 Hz, 1H), 9.28 (s, 1H).LC/MS: condition 1, retention time = 2.80 min LC/MS (ESI⁺) m/z; 272 [M +H]⁺ LC/MS (ESI⁻) m/z; 270 [M − H]⁻ 142  ¹H-NMR (DMSO-d₆) δ: 1.88-2.06(m, 4H), 2.19-2.32 (m, 2H), 2.92-3.02 (m, 2H), 3.10-3.14 (m, 1H), 3.62(s, 2H), 6.82 (br s, 1H), 7.13-7.25 (m, 2H), 7.27-7.40 (m, 1H),7.45-7.53 (m, 2H), 9.52 (s, 1H), 12.52 (br s, 1H). LC/MS: condition 3,retention time = 1.33 min LC/MS (ESI⁺) m/z; 351 [M + H]⁺ LC/MS (ESI⁻)m/z; 349 [M − H]⁻

TABLE^(a) 115 Ex Data 143 ¹H-NMR (DMSO-d₆) δ: 1.88-2.05 (m, 4H),2.21-2.35 (m, 2H), 2.94-3.03 (m, 2H), 3.10-3.24 (m, 1H), 3.68 (s, 2H),6.58 (d, J = 3.3 Hz, 1H), 6.81 (d, J = 3.3 Hz, 1H), 7.15-7.20 (m, 1H),7.46-7.52 (m, 1H), 9.52 (s, 1H), 12.52 (br s, 1H). LC/MS: condition 3,retention time = 1.52 min LC/MS (ESI⁺) m/z; 391 [M + H]⁺ LC/MS (ESI⁻)m/z; 389 [M − H]⁻ 144 LC/MS: condition 3, retention time = 1.22 minLC/MS (ESI⁺) m/z; 364 [M + H]⁺ LC/MS (ESI⁻) m/z; 362 [M − H]⁻ 145 ¹H-NMR(CDCl₃) δ: 1.97-2.11 (m, 2H), 2.12-2.33 (m, 4H), 2.97-3.10 (m, 2H),3.15-3.31 (m, 1H), 3.59 (s, 2H), 6.80-6.87 (m, 1H), 6.93 (dd, J = 8.4,2.7 Hz, 1H), 7.31 (t, J = 3.0 Hz, 1H), 7.80-7.90 (m, 1H), 8.15-8.20 (m,1H), 9.15 (br s, 1H), 9.23 (s, 1H). LC/MS: condition 3, retention time =1.58 min LC/MS (ESI⁺) m/z; 411, 413 [M + H]⁺ 146 ¹H-NMR (DMSO-d₆) δ:1.90-2.04 (m, 4H), 2.19-2.31 (m, 2H), 2.92-3.03 (m, 2H), 3.06-3.20 (m,1H), 3.57 (s, 2H), 6.30-6.35 (m, 1H), 6.40-6.45 (m, 1H), 6.78-6.84 (m,1H), 7.47-7.53 (m, 1H), 7.60 (s, 1H), 9.52 (s, 1H), 12.52 (br s, 1H).LC/MS: condition 3, retention time = 1.14 min LC/MS (ESI⁺) m/z; 323 [M +H]⁺ 147 ¹H-NMR (DMSO-d₆) δ: 1.84-2.06 (m, 4H), 2.15-2.33 (m, 2H),2.87-3.04 (m, 2H), 3.06-3.22 (m, 1H), 3.58 (s, 2H), 6.29 (d, J = 3.3 Hz,1H), 6.63 (d, J = 3.3 Hz, 1H), 6.81 (br s, 1H), 7.44-7.51 (m, 1H), 9.51(s, 1H), 12.52 (br s, 1H). LC/MS: condition 3, retention time = 1.44 minLC/MS (ESI⁺) m/z; 449 [M + H]⁺ LC/MS (ESI⁻) m/z; 447 [M − H]⁻ 148 ¹H-NMR(DMSO-d₆) δ: 1.86-2.10 (m, 4H), 2.18-2.33 (m, 2H), 2.94-3.10 (m, 2H),3.11-3.26 (m, 1H), 3.76 (s, 2H), 6.82 (br s, 1H), 6.91-7.03 (m, 2H),7.40-7.46 (m, 1H), 7.46-7.53 (m, 1H), 9.52 (s, 1H), 12.52 (br s, 1H).LC/MS: condition 3, retention time = 1.24 min LC/MS (ESI⁺) m/z; 339 [M +H]⁺ LC/MS (ESI⁻) m/z; 337 [M − H]⁻ 149 ¹H-NMR (DMSO-d₆) δ: 1.84-2.06 (m,4H), 2.17-2.33 (m, 2H), 2.88-3.04 (m, 2H), 3.05-3.22 (m, 1H), 3.57 (s,2H), 6.40 (d, J = 3.3 Hz, 1H), 6.51 (d, J = 3.3 Hz, 1H), 6.81 (br s,1H), 7.43-7.52 (m, 1H), 9.51 (s, 1H), 12.52 (br s, 1H). LC/MS: condition3, retention time = 1.39 min LC/MS (ESI⁺) m/z; 401, 403 [M + H]⁺ 150¹H-NMR (DMSO-d₆) δ: 1.85-2.08 (m, 4H), 2.20-2.37 (m, 2H), 2.94-3.05 (m,2H), 3.11-3.27 (m, 1H), 3.78 (s, 2H), 6.82 (br s, 1H), 7.46-7.53 (m,1H), 7.58 (s, 1H), 9.52 (s, 1H), 12.52 (br s, 1H). LC/MS: condition 3,retention time = 1.21 min LC/MS (ESI⁺) m/z; 374 [M + H]⁺ LC/MS (ESI⁻)m/z; 372 [M − H]⁻

TABLE^(a) 116 Ex Data 151 ¹H-NMR (DMSO-d₆) δ: 1.82-2.08 (m, 4H),2.12-2.28 (m, 2H), 2.86-3.05 (m, 2H), 3.05-3.20 (m, 1H), 3.46-3.65 (m,2H), 6.09-6.23 (m, 1H), 6.81 (br s, 1H), 7.48 (br s, 1H), 9.52 (s, 1H),12.52 (br s, 1H). LC/MS: condition 3, retention time = 0.63 min LC/MS(ESI⁺) m/z; 323 [M + H]⁺ LC/MS (ESI⁻) m/z; 321 [M − H]⁻ 152 ¹H-NMR(DMSO-d₆) δ: 1.87-2.12 (m, 4H), 2.25-2.42 (m, 2H), 2.97-3.10 (m, 2H),3.10-3.25 (m, 1H), 4.13 (s, 2H), 6.82 (br s, 1H), 7.45-7.53 (m, 1H),9.10 (s, 1H), 9.52 (s, 1H), 12.52 (br s, 1H). LC/MS: condition 3,retention time = 0.81 min LC/MS (ESI⁺) m/z; 341 [M + H]⁺ LC/MS (ESI⁻)m/z; 339 [M − H]⁻ 153 ¹H-NMR (DMSO-d₆) δ: 1.85-2.06 (m, 4H), 2.20-2.36(m, 2H), 2.92-3.05 (m, 2H), 3.12-3.27 (m, 1H), 3.80 (s, 2H), 6.82 (br s,1H), 7.48-7.53 (m, 1H), 7.59 (s, 1H), 9.52 (s, 1H), 12.52 (br s, 1H).LC/MS: condition 3, retention time = 1.58 min LC/MS (ESI⁺) m/z; 418, 420[M + H]⁺ LC/MS (ESI⁻) m/z; 416, 418 [M − H]⁻ 154 ¹H-NMR (DMSO-d₆) δ:1.96-2.03 (m, 4H), 2.23-2.29 (m, 2H), 2.94 (d, J = 11.4 Hz, 2H),3.16-3.21 (m, 1H), 3.63 (s, 2H), 6.82 (d, J = 2.4 Hz, 1H), 7.46-7.52 (m,2H), 7.74 (d, J = 7.5 Hz, 2H), 9.52 (s, 1H), 12.55 (br s, 1H). LC/MS:condition 3, retention time = 1.68 min LC/MS (ESI⁺) m/z; 419 [M + H]⁺LC/MS (ESI⁻) m/z; 417 [M − H]⁻ 155 ¹H-NMR (DMSO-d₆) δ: 1.95-2.06 (m,4H), 2.23-2.30 (m, 2H), 2.94 (d, J = 11.7 Hz, 2H), 3.16-3.19 (m, 1H),3.65 (s, 2H), 6.82 (d, J = 3.3 Hz, 1H), 7.49 (d, J = 3.3 Hz, 1H), 7.71(s, 2H), 7.84 (s, 1H), 9.52 (s, 1H). LC/MS: condition 3, retention time= 1.79 min LC/MS (ESI⁺) m/z; 435, 437 [M + H]⁺ LC/MS (ESI⁻) m/z; 433,435 [M − H]⁻ 156 ¹H-NMR (DMSO-d₆) δ: 1.96-2.04 (m, 4H), 2.23-2.30 (m,2H), 2.96 (d, J = 10.2 Hz, 2H), 3.22 (s, 3H), 3.67 (s, 2H), 6.81 (d, J =3.0 Hz, 1H), 7.49 (d, J = 3.3 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.91(d, J = 8.7 Hz, 2H), 9.49 (s, 1H). LC/MS: condition 3, retention time =1.12 min LC/MS (ESI⁺) m/z; 411 [M + H]⁺ LC/MS (ESI⁻) m/z; 409 [M − H]⁻157 ¹H-NMR (DMSO-d₆) δ: 1.95-2.07 (m, 4H), 2.27-2.33 (m, 2H), 2.98 (d, J= 11.7 Hz, 2H), 3.15-3.18 (m, 1H), 3.70 (s, 2H), 6.82 (d, J = 3.0 Hz,1H), 7.49 (d, J = 3.3 Hz, 1H), 7.61-7.68 (m, 2H), 7.76 (t, J = 7.7 Hz,1H), 9.51 (s, 1H). LC/MS: condition 3, retention time = 1.66 min LC/MS(ESI⁺) m/z; 419 [M + H]⁺ LC/MS (ESI⁻) m/z; 417 [M − H]⁻

TABLE^(a) 117 Ex Data 158 ¹H-NMR (DMSO-d₆) δ: 1.94-2.04 (m, 4H), 2.26(td, J = 10.8, 3.5 Hz, 2H), 2.95 (d, J = 11.7 Hz, 2H), 4.12 (s, 2H),6.82 (d, J = 3.0 Hz, 1H), 7.31 (dd, J = 8.4, 2.1 Hz, 1H), 7.41 (dd, J =9.9, 2.1 Hz, 1H), 7.49-7.54 (m, 2H), 9.53 (s, 1H), 12.54 (br s, 1H).LC/MS: condition 3, retention time = 1.54 min LC/MS (ESI⁺) m/z; 385, 387[M + H]⁺ 159 ¹H-NMR (DMSO-d₆) δ: 1.95-2.06 (m, 4H), 2.21-2.27 (m, 2H),2.94 (d, J = 11.4 Hz, 2H), 3.15-3.22 (m, 1H), 3.57 (s, 2H), 6.83 (d, J =3.3 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 10.8 Hz, 1H), 7.50(d, J = 3.3 Hz, 1H), 7.56 (t, J = 8.1 Hz, 1H), 9.53 (s, 1H), 12.54 (brs, 1H). LC/MS: condition 3, retention time = 1.58 min LC/MS (ESI⁺) m/z;385, 387 [M + H]⁺ LC/MS (ESI⁻) m/z; 383, 385 [M − H]⁻ 160 ¹H-NMR (CDCl₃)δ: 1.99-2.13 (m, 2H), 2.17-2.37 (m, 4H), 2.94-3.10 (m, 2H), 3.16-3.32(m, 1H), 3.59 (s, 2H), 6.80-6.88 (m, 1H), 7.21-7.35 (m, 2H), 7.41 (s,1H), 8.34 (d, J = 5.1 Hz, 1H), 9.18 (br s, 1H), 9.24 (s, 1H). LC/MS:condition 3, retention time = 1.16 min LC/MS (ESI⁺) m/z; 368, 370 [M +H]⁺ LC/MS (ESI⁻) m/z; 366, 368 [M − H]⁻ 161 ¹H-NMR (CDCl₃) δ: 2.00-2.16(m, 2H), 2.16-2.42 (m, 4H), 3.00-3.15 (m, 2H), 3.15-3.30 (m, 1H), 3.71(s, 2H), 6.80-6.90 (m, 1H), 7.28-7.37 (m, 1H), 7.53 (t, J = 5.4 Hz, 1H),8.38-8.50 (m, 2H), 9.11-9.30 (m, 2H). LC/MS: condition 3, retention time= 0.86 min LC/MS (ESI⁺) m/z; 352 [M + H]⁺ LC/MS (ESI⁻) m/z; 350 [M − H]⁻162 ¹H-NMR (CDCl₃) δ: 2.00-2.10 (m, 2H), 2.16-2.42 (m, 4H), 3.01-3.15(m, 2H), 3.16-3.32 (m, 1H), 3.74 (s, 2H), 6.80-6.89 (m, 1H), 7.29 (t, J= 3.0 Hz, 1H), 7.40 (td, J = 8.7, 3.0 Hz, 1H), 7.54 (dd, J = 8.4, 4.5Hz, 1H), 8.42 (d, J = 2.7 Hz, 1H), 9.08 (br s, 1H), 9.22 (s, 1H). LC/MS:condition 3, retention time = 1.17 min LC/MS (ESI⁺) m/z; 352 [M + H]⁺LC/MS (ESI⁻) m/z; 350 [M − H]⁻ 163 ¹H-NMR (CDCl₃) δ: 2.00-2.15 (m, 2H),2.19-2.50 (m, 4H), 3.02-3.14 (m, 2H), 3.18-3.33 (m, 1H), 3.70 (s, 2H),6.82-6.91 (m, 1H), 7.29-7.38 (m, 1H), 7.59 (d, J = 4.8 Hz, 1H), 8.48 (d,J = 4.8 Hz, 1H), 8.54 (s, 1H), 9.09 (br s, 1H), 9.23 (s, 1H). LC/MS:condition 3, retention time = 1.13 min LC/MS (ESI⁺) m/z; 368, 370 [M +H]⁺ 164 ¹H-NMR (DMSO-d₆) δ: 1.93-2.00 (m, 4H), 2.21-2.27 (m, 2H), 2.95(d, J = 10.5 Hz, 2H), 3.59 (s, 2H), 6.81 (d, J = 2.4 Hz, 1H), 7.10 (t, J= 8.4 Hz, 1H), 7.21 (t, J = 9.3 Hz, 1H), 7.48-7.56 (m, 2H), 9.52 (s,1H). LC/MS: condition 3, retention time = 1.39 min LC/MS (ESI⁺) m/z; 369[M + H]⁺

TABLE^(a) 118 Ex Data 165 ¹H-NMR (DMSO-d₆) δ: 1.95-2.07 (m, 4H), 2.23(td, J = 11.3, 3.0 Hz, 2H), 2.97 (d, J = 11.1 Hz, 2H), 3.62 (s, 2H),6.83 (d, J = 3.3 Hz, 1H), 7.25 (td, J = 8.6, 2.6 Hz, 1H), 7.43 (dd, J =8.9, 2.6 Hz, 1H), 7.50 (d, J = 3.3 Hz, 1H), 7.60 (dd, J = 8.6, 6.2 Hz,1H), 9.52 (s, 1H). LC/MS: condition 3, retention time = 1.50 min LC/MS(ESI⁺) m/z; 385, 387 [M + H]⁺ 166 ¹H-NMR (DMSO-d₆) δ: 1.91-2.06 (m, 4H),2.23 (td, J = 11.2, 3.1 Hz, 2H), 2.94 (d, J = 11.7 Hz, 2H), 3.55 (s,2H), 6.82 (d, J = 3.3 Hz, 1H), 7.19-7.24 (m, 1H), 7.35-7.45 (m, 2H),7.50 (d, J = 3.3 Hz, 1H), 9.52 (s, 1H). LC/MS: condition 3, retentiontime = 1.45 min LC/MS (ESI⁺) m/z; 369 [M + H]⁺ LC/MS (ESI⁻) m/z; 367 [M− H]⁻ 167 ¹H-NMR (DMSO-d₆) δ: 1.92-2.09 (m, 4H), 2.25-2.31 (m, 2H), 2.96(d, J = 12.0 Hz, 2H), 3.67 (s, 2H), 6.82 (d, J = 3.3 Hz, 1H), 7.43-7.52(m, 3H), 7.77 (t, J = 8.0 Hz, 1H), 9.51 (s, 1H). LC/MS: condition 3,retention time = 1.71 min LC/MS (ESI⁺) m/z; 419 [M + H]⁺ LC/MS (ESI⁻)m/z; 417 [M − H]⁻ 168 ¹H-NMR (DMSO-d₆) δ: 1.91-2.23 (m, 8H), 2.91 (t, J= 11.6 Hz, 1H), 3.46 (s, 2H), 3.69-3.71 (m, 2H), 3.96 (br s, 2H), 6.71(s, 1H), 6.90 (t, J = 6.8 Hz, 2H), 7.25 (t, J = 8.3 Hz, 2H), 7.43 (s,1H), 9.37 (s, 1H). LC/MS: condition 3, retention time = 1.15 min LC/MS(ESI⁺) m/z; 393 [M + H]⁺ 169 ¹H-NMR (CDCl₃) δ: 1.98-2.13 (m, 2H),2.13-2.34 (m, 4H), 2.98-3.16 (m, 2H), 3.16-3.32 (m, 1H), 3.59 (s, 2H),5.91 (tt, J = 56.1, 3.0 Hz, 1H), 6.81-6.90 (m, 1H), 7.18 (d, J = 8.4 Hz,2H), 7.27-7.33 (m, 1H), 7.41 (d, J = 8.4 Hz, 2H), 9.19 (br s, 1H), 9.23(s, 1H). LC/MS: condition 3, retention time = 1.72 min LC/MS (ESI⁺) m/z;449 [M + H]⁺ LC/MS (ESI⁻) m/z; 447 [M − H]⁻ 170 ¹H-NMR (CDCl₃) δ:1.96-2.12 (m, 2H), 2.12-2.35 (m, 4H), 3.00-3.16 (m, 2H), 3.16-3.31 (m,1H), 3.54 (s, 2H), 3.95 (s, 3H), 6.75 (d, J = 8.1 Hz, 1H), 6.81-6.90 (m,1H), 7.27-7.36 (m, 1H), 7.64 (dd, J = 8.4, 2.4 Hz, 1H), 8.11 (d, J = 2.1Hz, 1H), 9.23 (s, 1H), 9.51 (br s, 1H). LC/MS: condition 3, retentiontime = 1.22 min LC/MS (ESI⁺) m/z; 364 [M + H]⁺ 171 LC/MS: condition 3,retention time = 1.40 min LC/MS (ESI⁺) m/z; 386 [M + H]⁺

TABLE^(a) 119 Ex Data 172 ¹H-NMR (CDCl₃) δ: 1.12-1.28 (m, 2H), 1.62 (m,1H), 1.84-2.02 (m, 4H), 2.15 (m, 2H), 2.52 (dd, J = 12.0, 6.9 Hz, 1H),2.66 (dd, J = 12.0, 6.6 Hz, 1H), 2.98 (d, J = 12.9 Hz, 1H), 3.15 (tt, J= 12.3, 3.3 Hz, 1H), 3.54 (d, J = 12.9 Hz, 1H), 6.78 (m, 1H), 7.33-7.40(m, 4H), 7.60 (m, 2H), 9.22 (s, 1H), 9.45 (br s, 1H). LC/MS: condition1, retention time = 2.81 min LC/MS (ESI⁺) m/z; 459 [M + H]⁺ LC/MS (ESI⁻)m/z; 457 [M − H]⁻ 173 ¹H-NMR (DMSO-d₆) δ: 1.23-1.38 (m, 2H), 1.71-1.86(m, 2H), 1.95-2.09 (m, 4H), 3.08-3.23 (m, 3H), 6.82 (dd, J = 1.7, 3.3Hz, 1H), 6.86 (d, J = 9.2 Hz, 2H), 7.50 (t, J = 3.0 Hz, 1H), 7.59 (t, J= 5.6 Hz, 1H), 7.68 (d, J = 8.9 Hz, 2H), 9.52 (s, 1H), 12.54 (br s, 1H).LC/MS: condition 1, retention time = 4.30 min LC/MS (ESI⁺) m/z; 479 [M +H]⁺ LC/MS (ESI⁻) m/z; 477 [M − H]⁻ 174 ¹H-NMR (CD₃OD) δ: 1.17-1.33 (m,2H), 1.70-1.78 (m, 1H), 1.78-1.90 (m, 2H), 1.93-2.01 (m, 2H), 2.06-2.15(m, 2H), 2.66 (d, J = 7.0 Hz, 2H), 2.79-3.02 (m, 5H), 3.17 (tt, J =12.3, 3.3 Hz, 1H), 6.79 (d, J = 3.3 Hz, 1H), 7.16-7.32 (m, 6H), 7.38 (d,J = 3.3 Hz, 1H), 9.27 (br s, 1H). LC/MS: condition 1, retention time =2.75 min LC/MS (ESI⁺) m/z; 375 [M + H]⁺ LC/MS (ESI⁻) m/z; 373 [M − H]⁻175 ¹H-NMR (DMSO-d₆) δ: 1.24-1.39 (m, 2H), 1.71-1.87 (m, 3H), 2.01-2.09(m, 5H), 3.00 (d, J = 5.9 Hz, 2H), 3.13-3.25 (m, 1H), 5.94 (bs, 1H),6.57 (br s, 1H), 6.79-6.83 (m, 2H), 7.44 (d, J = 8.9 Hz, 1H), 7.50 (t, J= 3.0 Hz, 1H), 9.52 (s, 1H), 12.53 (br s, 1H). LC/MS: condition 1,retention time = 3.35 min LC/MS (ESI⁺) m/z; 455 [M + H]⁺ LC/MS (ESI⁻)m/z; 453 [M − H]⁻ 176 ¹H-NMR (DMSO-d₆) δ: 1.19-1.34 (m, 2H), 1.69-1.84(m, 3H), 1.96-2.07 (m, 4H), 2.93 (t, J = 5.6 Hz, 2H), 3.11-3.25 (m, 1H),5.89 (t, J = 5.6 Hz, 1H), 6.56-6.62 (m, 2H), 6.81 (dd, J = 3.0, 1.7 Hz,1H), 7.05-7.11 (m, 2H), 7.49 (t, J = 3.0 Hz, 1H), 9.52 (s, 1H), 12.53(br s, 1H). LC/MS: condition 1, retention time = 4.32 min LC/MS (ESI⁺)m/z; 381 [M + H]⁺ LC/MS (ESI⁻) m/z; 379 [M − H]⁻ 177 ¹H-NMR (CDCl₃) δ:1.24 (m, 2H), 1.76 (m, 1H), 1.86-2.17 (m, 6H), 2.57 (d, J = 6.6 Hz, 1H),3.16 (tt, J = 12.3, 3.6 Hz, 1H), 3.81 (s, 2H), 6.77 (d, J = 3.3 Hz, 1H),7.26-7.29 (m, 5H), 9.22 (s, 1H), 9.70 (br s, 1H). LC/MS: condition 1,retention time = 2.84 min LC/MS (ESI⁺) m/z; 395, 397 [M + H]⁺ LC/MS(ESI⁻) m/z; 393, 395 [M − H]⁻

TABLE^(a) 120 Ex Data 178 ¹H-NMR (CDCl₃) δ: 1.19 (m, 2H), 1.66 (m, 1H),1.90 (m, 4H), 2.12 (m, 2H), 2.57 (d, J = 6.6 Hz, 2H), 2.70-2.97 (m, 4H),3.16 (tt, J = 12.6, 3.3 Hz, 1H), 6.77 (d, J = 3.3 Hz, 1H), 7.15 (m, 3H),7.27 (m, 2H), 9.21 (s, 1H), 9.33 (br s, 1H). LC/MS: condition 1,retention time = 2.97 min LC/MS (ESI⁺) m/z; 409, 411 [M + H]⁺ LC/MS(ESI⁻) m/z; 407, 409 [M − H]⁻ 179 ¹H-NMR (CDCl₃) δ: 1.17-1.39 (m, 2H),1.71-2.28 (m, 7H), 2.86-3.06 (m, 4H), 3.10-3.30 (m, 1H), 3.33-3.55 (m,2H), 6.30-6.43 (m, 1H), 6.70-6.88 (m, 3H), 7.20-7.39 (m, 1H), 9.02 (brs, 1H), 9.22 (s, 1H). LC/MS: condition 1, retention time = 4.40 minLC/MS (ESI⁺) m/z; 391 [M + H]⁺ LC/MS (ESI⁻) m/z; 389 [M − H]⁻ 180 ¹H-NMR(CDCl₃) δ: 1.04-1.28 (m, 2H), 1.46-1.73 (m, 1H), 1.82-2.02 (m, 2H),2.04-2.23 (m, 4H), 2.39-2.60 (m, 6H), 2.84-3.00 (m, 4H), 3.09-3.28 (m,1H), 6.72-6.83 (m, 1H), 7.27-7.37 (m, 1H), 8.99 (br s, 1H), 9.21 (s,1H). LC/MS: condition 1, retention time = 3.38 min LC/MS (ESI⁺) m/z; 377[M + H]⁺ LC/MS (ESI⁻) m/z; 375 [M − H]⁻ 181 ¹H-NMR (CDCl₃) δ: 1.00-1.31(m, 2H), 1.50-1.80 (m, 1H), 1.81-2.18 (m, 7H), 2.24 (s, 6H), 2.26-2.59(m, 4H), 2.68-2.92 (m, 3H), 3.08-3.24 (m, 1H), 6.71-6.83 (m, 1H),7.17-7.33 (m, 1H), 9.00-9.40 (m, 1H), 9.21 (s, 1H). LC/MS: condition 1,retention time = 0.34 min LC/MS (ESI⁺) m/z; 368 [M + H]⁺ LC/MS (ESI⁻)m/z; 366 [M − H]⁻ 182 ¹H-NMR (CDCl₃) δ: 1.00-1.32 (m, 2H), 1.40-1.80 (m,1H), 1.82-2.21 (m, 7H), 2.29 (s, 3H), 2.58 (d, J = 6.6 Hz, 2H),3.08-3.25 (m, 1H), 3.76 (s, 2H), 5.89 (d, J = 2.1 Hz, 1H), 6.06 (d, J =3.0 Hz, 1H), 6.78 (d, J = 3.0 Hz, 1H), 7.17-7.32 (m, 1H), 9.00-9.40 (m,1H), 9.21 (s, 1H). LC/MS: condition 1, retention time = 2.49 min LC/MS(ESI⁺) m/z; 365 [M + H]⁺ LC/MS (ESI⁻) m/z; 363 [M − H]⁻ 183 ¹H-NMR(CDCl₃) δ: 1.11-1.35 (m, 2H), 1.40-1.81 (m, 1H), 1.83-2.25 (m, 7H), 2.57(s, 3H), 2.62 (d, J = 6.6 Hz, 2H), 3.07-3.27 (m, 1H), 3.96 (s, 2H),6.70-6.85 (m, 1H), 7.10-7.37 (m, 1H), 8.35-8.46 (m, 1H), 8.49-8.59 (m,1H), 9.00-9.40 (m, 1H), 9.21 (s, 1H). LC/MS: condition 1, retention time= 0.77 min LC/MS (ESI⁺) m/z; 377 [M + H]⁺ LC/MS (ESI⁻) m/z; 375 [M − H]⁻184 ¹H-NMR (CDCl₃) δ: 1.11-1.38 (m, 5H), 1.55-2.35 (m, 9H), 2.40-2.85(m, 4H), 3.09-3.27 (m, 1H), 3.72-3.92 (m, 1H), 6.80 (d, J = 3.3 Hz, 1H),7.30 (d, J = 3.3 Hz, 1H), 8.60-10.00 (m, 1H), 9.23 (s, 1H). LC/MS:condition 1, retention time = 0.39 min LC/MS (ESI⁺) m/z; 329 [M + H]⁺LC/MS (ESI⁻) m/z; 327 [M − H]

TABLE^(a) 121 Ex Data 185 ¹ H-NMR (CDCl₃) δ: 1.10-1.50 (m, 5H),1.55-2.35 (m, 9H), 2.40-2.90 (m, 4H), 3.10-3.31 (m, 1H), 3.75-4.00 (m,1H), 6.80 (d, J = 3.3 Hz, 1H), 7.30 (d, J = 3.3 Hz, 1H), 8.80-10.00 (m,1H), 9.23 (s, 1H). LC/MS: condition 1, retention time = 0.37 min LC/MS(ESI⁺) m/z; 329 [M + H]⁺ LC/MS (ESI⁻) rn/z; 327 [M − H]⁻ 186 ¹H-NMR(CD₃OD) δ: 1.30 (m, 2H), 1.70-2.15 (m, 7H), 2.74 (t, J = 6.6 Hz, 2H),2.92 (d, J = 6.6 Hz, 2H), 3.21 (tt, J = 12.0, 4.2 Hz, 1H), 4.92 (m, 1H),6.82 (d, J = 3.3 Hz, 1H), 6.83-7.43 (m, 6H), 9.30 (s, 1H). LC/MS:condition 1, retention time = 2.52 min LC/MS (ESI⁺) m/z; 391 [M + H]⁺,LC/MS (ESI⁻) m/z; 389 [M − H]⁻ 187 ¹H-NMR (CDCl₃) δ: 1.07-1.31 (m, 2H),1.47-1.74 (m, 1H), 1.80-2.32 (m, 8H), 2.34-2.49 (m, 2H), 2.55-2.80 (m,3H), 2.88-3.25 (m, 3H), 6.71-6.86 (m, 1H), 7.18-7.39 (m, 1H), 9.01 (brs, 1H), 9.21 (s, 1H). LC/MS: condition 3, retention time = 1.14 minLC/MS (ESI⁺) m/z; 350 [M + H]⁺ LC/MS (ESI⁻) m/z; 348 [M − H]⁻ 188 ¹H-NMR(CDCl₃) δ: 1.10-1.40 (m, 3H), 1.50-1.80 (m, 1H), 1.83-2.24 (m, 6H), 2.68(d, J = 6.0 Hz, 2H), 3.06-3.50 (m, 3H), 6.70-6.85 (m, 1H), 7.18-7.35 (m,1H), 9.10 (br s, 1H), 9.22 (s, 1H). LC/MS: condition 3, retention time =1.30 min LC/MS (ESI⁺) m/z; 353 [M + H]⁺ 189 ¹H-NMR (CDCl₃) δ: 1.11-1.45(m, 3H), 1.78-2.36 (m, 6H), 2.91-3.31 (m, 5H), 3.00 (s, 3H), 3.52-3.80(m, 2H), 6.40 (d, J = 8.6 Hz, 1H), 6.70-6.90 (m, 1H), 7.20-7.38 (m, 1H),7.50 (s, 1H), 7.54-7.73 (m, 1H), 9.22 (s, 1H), 9.30 (br s, 1H). LC/MS:condition 3, retention time = 2.13 min LC/MS (ESI⁺) m/z; 451 [M + H]⁺,LC/MS (ESI⁻) m/z; 449 [M − H]⁻ 190 ¹H-NMR (CDCl₃) δ: 1.15-1.40 (m, 3H),1.80-2.30 (m, 6H), 2.68 (s, 6H), 3.00-3.30 (m, 5H), 3.55-3.74 (m, 2H),6.40 (d, J = 8.6 Hz, 1H), 6.79 (t, J = 2.4 Hz, 1H), 7.29 (t, J = 3.0 Hz,1H), 7.34 (s, 1H), 7.50 (dd, J = 8.3, 1.2 Hz, 1H), 9.09 (br s, 1H), 9.22(s, 1H). LC/MS: condition 3, retention time = 2.35 min LC/MS (ESI⁺) m/z;480 [M + H]⁺, LC/MS (ESI⁻) m/z; 478 [M − H]⁻ 191 ¹H-NMR (CDCl₃) δ:1.00-1.40 (m, 3H), 1.50-2.40 (m, 7H), 2.51-2.93 (m, 4H), 3.00-3.23 (m,1H), 3.25-3.68 (m, 6H), 4.50-4.89 (m, 1H), 6.67-6.84 (m, 1H), 7.20-7.42(m, 1H), 9.20 (s, 1H), 9.97 (br s, 1H). LC/MS: condition 3, retentiontime = 1.13 min LC/MS (ESI⁺) m/z; 383 [M + H]⁺ LC/MS (ESI⁻) m/z; 381 [M− H]⁻ 192 ¹H-NMR (DMSO-d₆) δ: 1.13-1.42 (m, 2H), 1.64-2.15 (m, 6H),2.78-3.60 (m, 9H), 6.81 (s, 1H), 7.40-7.62 (m, 2H), 8.99 (s, 1H), 9.08(br s, 1H), 9.52 (s, 1H), 12.56 (s, 1H), 14.44 (br s, 1H). LC/MS:condition 3, retention time = 0.68 min LC/MS (ESI⁺) m/z; 365 [M + H]⁺LC/MS (ESI⁻) m/z; 363 [M − H]⁻

TABLE^(a) 122 Ex Data 193 ¹H-NMR (DMSO-d₆) δ: 1.10-1.26 (m, 2H),1.51-1.63 (m, 1H), 1.75 (qd, J = 12.2, 3.3 Hz, 2H), 1.92-2.04 (m, 4H),2.42 (d, J = 6.6 Hz, 2H), 3.13 (tt, J = 12.6, 3.3 Hz, 1H), 3.72 (s, 2H),6.80 (d, J = 3.6 Hz, 1H), 7.22 (tt, J = 6.9, 2.0 Hz, 1H), 7.28-7.38 (m,4H), 7.49 (d, J = 3.3 Hz, 1H), 9.51 (s, 1H), 12.52 (br s, 1H). LC/MS:condition 1, retention time = 2.67 min LC/MS (ESI⁺) m/z; 361 [M + H]⁺LC/MS (ESI⁻) m/z; 359 [M − H]⁻ 194a ¹H-NMR (DMSO-d₆) δ: 1.55-1.70 (m,4H), 1.81-1.92 (m, 2H), 1.99-2.07 (m, 1H), 2.20-2.35 (m, 2H), 2.84-2.89(m, 1H), 3.16-3.29 (m, 1H), 3.75 (s, 2H), 7.13 (d, J = 3.3 Hz, 1H), 7.23(tt, J = 6.9, 1.7 Hz, 1H), 7.31-7.43 (m, 5H), 9.50 (s, 1H), 12.49 (br s,1H). LC/MS: condition 1, retention time = 2.22 min LC/MS (ESI⁺) m/z; 347[M + H]⁺ LC/MS (ESI⁻) m/z; 345 [M − H]⁻ 194b ¹H-NMR (DMSO-d₆) δ:1.26-1.42 (m, 2H), 1.75 (qd, J = 12.7, 3.3 Hz, 2H), 1.95-2.14 (m, 5H),2.51-2.62 (m, 1H), 3.15 (tt, J = 12.3, 3.7 Hz, 1H), 3.79 (s, 2H), 6.79(d, J = 3.3 Hz, 1H), 7.22 (tt, J = 7.4, 1.6 Hz, 1H), 7.28-7.39 (m, 4H),7.48 (d, J = 3.3 Hz, 1H), 9.50 (s, 1H), 12.51 (br s, 1H). LC/MS:condition 1, retention time = 1.47 min LC/MS (ESI⁺) m/z; 347 [M + H]⁺LC/MS (ESI⁻) m/z; 345 [M − H]⁻ 195a ¹H-NMR (DMSO-d₆) δ: 1.54-1.69 (m,4H), 1.80-1.90 (m, 2H), 2.18-2.33 (m, 2H), 2.81-2.88 (m, 1H), 3.14-3.17(m, 1H), 3.18-3.30 (m, 1H), 3.73 (s, 2H), 7.08-7.20 (m, 3H), 7.38-7.46(m, 3H), 9.50 (s, 1H), 12.49 (br s, 1H). LC/MS: condition 1, retentiontime = 2.55 min LC/MS (ESI⁺) m/z; 365 [M + H]⁺ LC/MS (ESI⁻) m/z; 363 [M− H]⁻ 195b ¹H-NMR (DMSO-d₆) δ: 1.25-1.41 (m, 2H), 1.67-1.83 (m, 2H),1.95-2.12 (m, 5H), 2.51-2.60 (m, 1H), 3.08-3.20 (m, 1H), 3.78 (s, 2H),6.80 (d, J = 3.3 Hz, 1H), 7.10-7.18 (m, 2H), 7.37-7.44 (m, 2H), 7.49 (d,J = 3.3 Hz, 1H), 9.51 (s, 1H), 12.53 (br s, 1H). LC/MS: condition 1,retention time = 1.03 min LC/MS (ESI⁺) m/z; 365 [M + H]⁺ LC/MS (ESI⁻)m/z; 363 [M − H]⁻ 196a ¹H-NMR (CDCl₃) δ: 1.77-1.92 (m, 6H), 2.19 (m,2H), 2.81 (m, 1H), 3.00 (d, J = 13.2 Hz, 1H), 3.35 (m, 1H), 3.55 (d, J =13.2 Hz, 1H), 6.75 (d, J = 3.3 Hz, 1H), 7.30 (m, 1H), 7.37 (m, 3H), 7.60(m, 2H), 9.22 (s, 1H), 9.44 (br s, 1H). LC/MS: condition 1, retentiontime = 2.75 min LC/MS (ESI⁺) m/z; 445 [M + H]⁺ LC/MS (ESI⁻) m/z; 443 [M− H]⁻

TABLE^(a) 123 Ex Data 196b ¹H-NMR (CDCl₃) δ: 1.26-1.38 (m, 2H), 1.92 (m,2H), 2.15 (m, 4H), 2.62 (tt, J = 11.4, 3.6 Hz, 1H), 3.02 (d, J = 13.2Hz, 1H), 3.15 (tt, J = 12.0, 3.3 Hz, 1H), 3.60 (d, J = 13.2 Hz, 1H),6.74 (d, J = 3.3 Hz, 1H), 7.30 (d, J = 2.7 Hz, 1H), 7.39 (m, 3H), 7.61(m, 2H), 9.22 (s, 1H), 9.63 (br s, 1H). LC/MS: condition 1, retentiontime = 2.57 min LC/MS (ESI⁺) m/z; 445 [M + H]⁺ LC/MS (ESI⁻) m/z; 443 [M− H]⁻ 197a ¹H-NMR (DMSO-d₆) δ: 1.56-1.71 (m, 4H), 1.80-1.91 (m, 2H),2.13-2.35 (m, 3H), 2.82-2.88 (m, 1H), 3.19-3.30 (m, 1H), 3.75 (s, 2H),7.10 (d, J = 3.3 Hz, 1H), 7.39-7.47 (m, 5H), 9.52 (s, 1H), 12.51 (br s,1H). LC/MS: condition 1, retention time = 2.75 min LC/MS (ESI⁺) m/z; 381[M + H]⁺ LC/MS (ESI⁻) m/z; 379 [M − H]⁻ 197b ¹H-NMR (DMSO-d₆) δ:1.26-1.41 (m, 2H), 1.75 (qd, J = 12.6, 2.3 Hz, 2H), 1.95-2.12 (m, 5H),2.54 (tt, J = 10.9, 3.3 Hz, 1H), 3.14 (tt, J = 11.9, 3.3 Hz, 1H), 3.78(s, 2H), 6.80 (d, J = 3.3 Hz, 1H), 7.34-7.43 (m, 4H), 7.49 (d, J = 3.0Hz, 1H), 9.51 (s, 1H), 12.53 (br s, 1H). LC/MS: condition 1, retentiontime = 2.62 min LC/MS (ESI⁺) m/z; 381 [M + H]⁺ LC/MS (ESI⁻) m/z; 379 [M− H]⁻ 198b ¹H-NMR (CDCl₃) δ: 1.33 (m, 2H), 1.94 (m, 2H), 2.14 (m, 4H),2.69 (m, 1H), 2.83 (t, J = 6.9 Hz, 2H), 2.99 (t, J = 6.9 Hz, 2H), 3.16(tt, J = 12.0, 3.3 Hz, 1H), 7.75 (d, J = 3.3 Hz, 1H), 7.16 (m, 2H), 7.29(m, 3H), 9.21 (s, 1H), 9.46 (br s, 1H). LC/MS: condition 1, retentiontime = 2.87 min LC/MS (ESI⁺) m/z; 395, 397 [M + H]⁺ LC/MS (ESI⁻) m/z;393, 395 [M − H]⁻ 199b ¹H-NMR (CDCl₃) δ: 1.26-1.38 (m, 2H), 1.92 (m,2H), 2.15 (m, 4H), 2.62 (tt, J = 11.1, 3.3 Hz, 1H), 2.98 (d, J = 12.9Hz, 1H), 3.16 (tt, J = 12.6, 3.3 Hz, 1H), 3.60 (d, J = 13.2 Hz, 1H),6.74 (d, J = 3.3 Hz, 1H), 7.30-7.39 (m, 3H), 7.55 (m, 2H), 9.23 (s, 1H),9.77 (br s, 1H). LC/MS: condition 1, retention time = 2.97 min LC/MS(ESI⁺) m/z; 479, 481 [M + H]⁺ LC/MS (ESI⁻) m/z; 477, 479 [M − H]⁻ 200b¹H-NMR (CDCl₃) δ: 1.26-1.43 (m, 2H), 1.92 (m, 2H), 2.15 (m, 4H), 2.63(tt, J = 11.4, 3.3 Hz, 1H), 3.00 (d, J = 13.2 Hz, 1H), 3.17 (tt, J =12.3, 3.3 Hz, 1H), 3.60 (d, J = 13.2 Hz, 1H), 6.74 (d, J = 3.3 Hz, 1H),7.09 (t, J = 8.4 Hz, 2H), 7.32 (d, J = 3.0 Hz, 1H), 7.59(dd, J = 8.7,5.7 Hz, 2H), 9.24 (s, 1H), 10.00 (br s, 1H). LC/MS: condition 1,retention time = 2.79 min LC/MS (ESI⁺) m/z; 463 [M + H]⁺ LC/MS (ESI⁻)m/z; 461 [M − H]⁻

TABLE^(a) 124 Ex Data 201b ¹H-NMR (DMSO-d₆) δ: 1.19-1.35 (m, 2H), 1.78(qd, J = 12.6, 4.0 Hz, 2H), 1.92-2.07 (m, 4H), 2.51-2.61 (m, 1H),2.68-2.75 (m, 2H), 2.78-2.86 (m, 2H), 3.07-3.19 (m, 2H), 6.80 (d, J =3.6 Hz, 1H), 7.06-7.14 (m, 2H), 7.24-7.31 (m, 2H), 7.49 (d, J = 3.6 Hz,1H), 9.51 (s, 1H), 12.52 (br s, 1H). LC/MS: condition 1, retention time= 2.57 min LC/MS (ESI⁺) m/z; 379 [M + H]⁺ LC/MS (ESI⁻) m/z; 377 [M − H]⁻202b ¹H-NMR (CD₃OD) δ: 1.52 (m, 2H), 1.90 (m, 2H), 2.18 (m, 4H),2.80-3.00 (m, 3H), 3.23 (m, 1H), 4.92 (m, 1H), 6.82 (d, J = 3.3 Hz, 1H),6.83-7.43 (m, 6H), 9.29 (s, 1H). LC/MS: condition 1, retention time =0.94 min LC/MS (ESI⁺) m/z; 377 [M + H]⁺ LC/MS (ESI⁻) m/z; 375 [M − H]⁻203b ¹H-NMR (CD₃OD) δ: 1.43 (m, 2H), 1.90 (m, 2H), 2.12 (m, 4H), 2.71(tt, J = 11.1, 3.9 Hz, 1H), 2.79-2.91 (m, 2H), 3.21 (tt, J = 12.3, 3.6Hz, 1H), 4.79 (m, 1H), 6.81 (d, J = 3.3 Hz, 1H), 7.25-7.42 (m, 6H), 9.27(s, 1H). LC/MS: condition 1, retention time = 1.29 min LC/MS (ESI⁺) m/z;377 [M + H]⁺ LC/MS (ESI⁻) m/z; 375 [M − H]⁻ 204b ¹H-NMR (CD₃OD) δ: 1.57(m, 2H), 1.93 (m, 2H), 2.20 (m, 4H), 2.95-3.09 (m, 3H), 3.24 (m, 1H),4.90 (m, 1H), 6.83 (d, J = 3.3 Hz, 1H), 7.27-7.44 (m, 6H), 9.30 (s, 1H).LC/MS: condition 1, retention time = 1.29 min LC/MS (ESI⁺) m/z; 377 [M +H]⁺ LC/MS (ESI⁻) m/z; 375 [M − H]⁻ 205 LC/MS: condition 1, retentiontime = 3.80, 4.15 min (cis/trans mixture) LC/MS (ESI⁺) m/z; 367 [M + H]⁺LC/MS (ESI⁻) m/z; 365 [M − H]⁻ 206 ¹H-NMR (DMSO-d₆) δ: 1.72-1.88 (m,4H), 1.96-2.13 (m, 4H), 3.19-3.38 (m, 2H), 6.89 (d, J = 3.3 Hz, 1H),7.10-7.18 (m, 2H), 7.51 (d, J = 3.0 Hz, 1H), 7.63-7.70 (m, 2H), 9.54 (s,1H), 9.98 (s, 1H), 12.55 (br s, 1H). LC/MS: condition 1, retention time= 3.63 min LC/MS (ESI⁺) m/z; 379 [M + H]⁺ LC/MS (ESI⁻) m/z; 377 [M − H]⁻207 ¹H-NMR (DMSO-d₆) δ: 1.66-1.82 (m, 4H), 1.89-1.97 (m, 2H), 2.00-2.09(m, 2H), 2.32-2.43 (m, 1H), 3.14-3.25 (m, 1H), 4.27 (d, J = 6.3 Hz, 2H),6.86 (dd, J = 3.0, 1.7 Hz, 1H), 7.12-7.20 (m, 2H), 7.26-7.32 (m, 2H),7.50 (t, J = 3.0 Hz, 1H), 8.31-8.37 (m, 1H), 9.52 (s, 1H), 12.53 (br s,1H). LC/MS: condition 1, retention time = 3.49 min LC/MS (ESI⁺) m/z; 393[M + H]⁺ LC/MS (ESI⁻) m/z; 391 [M − H]⁻

TABLE^(a) 125 Ex Data 208 ¹H-NMR (DMSO-d₆) δ: 1.60-1.88 (m, 6H),1.98-2.06 (m, 2H), 2.20-2.31 (m, 1H), 2.72 (t, J = 6.9 Hz, 2H),3.11-3.22 (m, 1H), 3.24-3.31 (m, 2H), 6.84 (dd, J = 3.0, 1.7 Hz, 1H),7.07-7.16 (m, 2H), 7.21-7.28 (m, 2H), 7.50 (t, J = 3.0 Hz, 1H), 7.85 (t,J = 5.6 Hz, 1H), 9.52 (s, 1H), 12.53 (br s, 1H). LC/MS: condition 1,retention time = 3.59 min LC/MS (ESI⁺) m/z; 407 [M + H]⁺ LC/MS (ESI⁻)m/z; 405 [M − H]⁻ 209 LC/MS: condition 1, retention time = 3.00 minLC/MS (ESI⁺) m/z; 357 [M + H]⁺ LC/MS (ESI⁻) m/z; 355 [M − H]⁻ 210 ¹H-NMR(DMSO-d₆) δ: 1.78-1.98 (m, 3H), 2.21 (br s, 1H), 2.91 (br s, 3H), 3.63(s, 2H), 6.57 (s, 1H), 7.17 (s, 1H), 7.57 (d, J = 7.5 Hz, 2H), 7.82 (d,J = 7.5 Hz, 2H), 8.31 (s, 1H), 8.83 (s, 1H), 11.94 (br s, 1H). LC/MS:condition 3, retention time = 1.21 min LC/MS (ESI⁺) m/z; 357 [M + H]⁺211 ¹H-NMR (CDCl₃) δ: 2.46-2.63 (m, 2H), 3.58-4.09 (m, 5H), 5.18 (s,2H), 6.76 (s, 1H), 7.31-7.40 (m, 6H), 9.19 (br s, 1H), 9.24 (s, 1H).LC/MS: condition 3, retention time = 2.05 min LC/MS (ESI⁺) m/z; 363 [M +H]⁺ LC/MS (ESI⁻) m/z; 361 [M − H]⁻ 212 ¹H-NMR (CDCl₃) δ: 2.02-2.41 (m,5H), 2.45-2.73 (m, 3H), 3.02 (d, J = 10.7 Hz, 1H), 3.21-3.36 (m, 1H),3.37 (d, J = 9.4 Hz, 1H), 4.86 (dd, J = 10.7, 3.4 Hz, 1H), 6.82 (d, J =3.0 Hz, 1H), 7.32 (br s, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 8.3Hz, 2H), 9.14 (br s, 1H), 9.25 (s, 1H). LC/MS: condition 1, retentiontime = 2.67 min LC/MS (ESI⁺) m/z; 431 [M + H]⁺ LC/MS (ESI⁻) m/z; 429 [M− H]⁻

TABLE^(a) 126 Ex Data 213 LC/MS: condition 3, retention time = 1.35 minLC/MS (ESI⁺) m/z; 388 [M + H]⁺ LC/MS (ESI⁻) m/z; 386 [M − H]⁻ 214 ¹H-NMR(DMSO-d₆) δ: 1.86-2.05 (m, 4H), 2.19-2.32 (m, 2H), 2.88-3.00 (m, 2H),3.37-3.50 (m, 1H), 3.60 (s, 2H), 6.80-6.85 (m, 1H), 7.47-7.54 (m, 2H),7.80-7.89 (m, 1H), 8.38-8.42 (m, 1H), 9.53 (s, 1H), 12.54 (br s, 1H).LC/MS: condition 3, retention time = 1.21 min LC/MS (ESI⁺) m/z; 368 [M +H]⁺ LC/MS (ESI⁻) m/z; 366 [M − H]⁻ 215 ¹H-NMR (DMSO-d₆) δ: 1.88-2.08 (m,4H), 2.13-2.29 (m, 2H), 2.94-3.07 (m, 2H), 3.10-3.22 (m, 3H), 6.10-6.22(m, 1H), 6.37-6.53 (m, 3H), 6.81 (d, J = 3.2 Hz, 1H), 7.49 (d, J = 3.2Hz, 1H), 7.60 (s, 1H), 9.52 (s, 1H), 12.52 (br s, 1H). LC/MS: condition3, retention time = 1.40 min LC/MS (ESI⁺) m/z; 349 [M + H]⁺ 216 ¹H-NMR(DMSO-d₆) δ: 1.84-2.05 (m, 4H), 2.05-2.18 (m, 2H), 2.24 (s, 3H),2.86-2.96 (m, 2H), 3.15-3.18 (m, 1H), 6.80 (d, J = 3.2 Hz, 1H), 7.49 (d,J = 3.2 Hz, 1H), 9.52 (s, 1H), 12.53 (br s, 1H). LC/MS: condition 3,retention time = 0.47 min LC/MS (ESI⁺) m/z; 257 [M + H]⁺ 217 ¹H-NMR(DMSO-d₆) δ: 1.85-2.06 (m, 4H), 2.18-2.32 (m, 2H), 2.70-2.76 (m, 1H),2.90-3.03 (m, 2H), 3.68 (s, 2H), 6.82 (d, J = 3.3 Hz, 1H), 7.45-7.62 (m,4H), 9.52 (s, 1H), 12.53 (br s, 1H), 13.22 (br s, 1H). LC/MS: condition3, retention time = 1.35 min LC/MS (ESI⁺) m/z; 407, 409 [M + H]⁺ 218¹H-NMR (DMSO-d₆) δ: 1.88-2.15 (m, 4H), 2.25-2.40 (m, 2H), 2.97-3.10 (m,2H), 3.14-3.30 (m, 1H), 3.83 (s, 2H), 6.84 (d, J = 3.0 Hz, 1H), 7.50 (d,J = 3.0 Hz, 1H), 7.89-7.96 (m, 1H), 8.00-8.15 (m, 2H), 8.89-9.00 (m,2H), 9.52 (s, 1H), 12.53 (br s, 1H). LC/MS: condition 3, retention time= 1.15 min LC/MS (ESI⁺) m/z; 385 [M + H]⁺ 219 ¹H-NMR (DMSO-d₆) δ:1.82-2.08 (m, 4H), 2.20-2.32 (m, 2H), 2.94-3.10 (m, 2H), 3.10-3.23 (m,1H), 3.50 (s, 2H), 6.80 (d, J = 3.2 Hz, 1H), 7.48 (d, J = 3.2 Hz, 1H),8.01 (s, 1H), 8.31 (s, 1H), 9.52 (s, 1H), 12.53 (br s, 1H). LC/MS:condition 3, retention time = 0.63 min LC/MS (ESI⁺) m/z; 324 [M + H]⁺220 ¹H-NMR (DMSO-d₆) δ: 1.93-2.00 (m, 4H), 2.16-2.22 (m, 2H), 2.93 (d, J= 11.4 Hz, 2H), 3.16 (s, 1H), 3.53 (s, 2H), 6.78 (dd, J = 3.3, 1.2, 1H),7.13 (d, J = 8.4 Hz, 2H), 7.20 (s, 1H), 7.39 (d, J = 7.8 Hz, 2H),7.45-7.47 (m, 1H), 9.48 (s, 1H). LC/MS: condition 3, retention time =1.54 min LC/MS (ESI⁺) m/z; 399 [M + H]⁺

TABLE^(a) 127 Ex Data 221 ¹H-NMR (DMSO-d₆) δ: 1.95-2.06 (m, 4H), 2.23(t, J = 9.8 Hz, 2H), 2.97 (d, J = 10.8 Hz, 2H), 3.16 (s, 1H), 3.59 (s,2H), 6.80 (d, J = 3.3 Hz, 1H), 7.08 (s, 1H), 7.47-7.49 (m, 3H), 7.61 (d,J = 8.4 Hz, 2H), 7.72 (s, 1H), 8.22 (s, 1H), 9.49 (s, 1H). LC/MS:condition 3, retention time = 0.48 min LC/MS (ESI⁺) m/z; 399 [M + H]⁺222 ¹H-NMR (DMSO-d₆) δ: 1.92-2.09 (m, 4H), 2.25-2.32 (m, 2H), 2.94 (d, J= 11.1 Hz, 2H), 3.68 (s, 2H), 6.82 (d, J = 2.7 Hz, 1H), 7.43-7.54 (m,3H), 7.91 (t, J = 7.5 Hz, 1H), 9.50 (s, 1H). LC/MS: condition 3,retention time = 1.35 min LC/MS (ESI⁺) m/z; 376 [M + H]⁺ LC/MS (ESI⁻)m/z; 374 [M − H]⁻ 223 ¹H-NMR (DMSO-d₆) δ: 1.93-2.05 (m, 4H), 2.24 (td, J= 11.1, 3.3 Hz, 2H), 2.92 (d, J = 11.7 Hz, 2H), 3.58 (s, 2H), 6.81 (d, J= 2.7 Hz, 1H), 7.47-7.53 (m, 2H), 7.75-7.80 (m, 1H), 7.86 (dd, J = 6.3,2.1 Hz, 1H), 9.51 (s, 1H), 12.51 (br s, 1H). LC/MS: condition 3,retention time = 1.37 min LC/MS (ESI⁺) m/z; 376 [M + H]⁺ LC/MS (ESI⁻)m/z; 374 [M − H]⁻ 224 LC/MS: condition 3, retention time = 1.63 minLC/MS (ESI⁺) m/z; 437 [M + H]⁺ LC/MS (ESI⁻) m/z; 435 [M − H]⁻ 225 ¹H-NMR(DMSO-d₆) δ: 1.89-2.08 (m, 4H), 2.11-2.32 (m, 2H), 2.89-3.03 (m, 2H),3.12-3.26 (m, 1H), 3.40-3.52 (m, 2H), 4.55 (s, 2H), 6.77-7.00 (m, 4H),7.47-7.53 (m, 1H), 9.52 (s, 1H), 10.66 (br s, 1H), 12.53 (br s, 1H).LC/MS: condition 3, retention time = 1.23 min LC/MS (ESI⁺) m/z; 404 [M +H]⁺ LC/MS (ESI⁻) m/z; 402 [M − H]⁻ 226 ¹H-NMR (DMSO-d₆) δ: 1.90-1.97 (m,4H), 2.13 (t, J = 10.7 Hz, 2H), 2.69 (t, J = 6.6 Hz, 2H), 2.91-2.96 (m,5H), 3.41 (s, 2H), 3.64 (t, J = 6.8 Hz, 2H), 6.73 (d, J = 8.4 Hz, 2H),6.79 (d, J = 3.3 Hz, 1H), 7.15 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 3.0 Hz,1H), 9.50 (s, 1H). LC/MS: condition 3, retention time = 1.48 min LC/MS(ESI⁺) m/z; 415 [M + H]⁺ 227 ¹H-NMR (DMSO-d₆) δ: 1.87-2.08 (m, 4H),2.15-2.30 (m, 2H), 2.90-3.00 (m, 2H), 3.10-3.26 (m, 1H), 3.57 (s, 2H),6.82 (d, J = 3.3 Hz, 1H), 7.19 (dd, J = 1.5, 8.5 Hz, 1H), 7.36 (d, J =8.5 Hz, 1H), 7.39 (d, J = 1.5 Hz, 1H), 7.49 (d, J = 3.3 Hz, 1H), 9.52(s, 1H), 12.52 (br s, 1H). LC/MS: condition 3, retention time = 1.66 minLC/MS (ESI⁺) m/z; 413 [M + H]⁺ LC/MS (ESI⁻) m/z; 411 [M − H]⁻

TABLE^(a) 128 Ex Data 228 ¹H-NMR (DMSO-d₆) δ: 1.87-2.08 (m, 4H),2.18-2.32 (m, 2H), 2.90-3.03 (m, 2H), 3.04-3.22 (m, 1H), 3.55 (s, 2H),6.39-6.48 (m, 2H), 6.81 (d, J = 3.0 Hz, 1H), 7.48 (d, J = 3.0 Hz, 1H),9.51 (s, 1H), 12.52 (br s, 1H). LC/MS: condition 3, retention time =1.37 min LC/MS (ESI⁺) m/z; 357, 359 [M + H]⁺ 229 ¹H-NMR (DMSO-d₆) δ:1.86-2.06 (m, 4H), 2.20-2.34 (m, 2H), 2.92-3.02 (m, 2H), 3.10-3.24 (m,1H), 3.67 (s, 2H), 6.80-6.85 (m, 1H), 7.14-7.33 (m, 3H), 7.44-7.50 (m,1H), 9.52 (s, 1H), 12.52 (br s, 1H). LC/MS: condition 3, retention time= 1.60 min LC/MS (ESI⁺) m/z; 413 [M + H]⁺ LC/MS (ESI⁻) m/z; 411 [M − H]⁻230 ¹H-NMR (DMSO-d₆) δ: 1.94-2.17 (m, 4H), 3.46-3.65 (m, 3H), 4.25-4.38(m, 2H), 6.91 (d, J = 3.3 Hz, 1H), 7.10 (t, J = 6.9 Hz, 1H), 7.31 (t, J= 6.9 Hz, 2H), 7.51 (d, J = 7.5 Hz, 2H), 7.52 (s, 2H), 9.54 (s, 1H),12.56 (br s, 1H). LC/MS: condition 3, retention time = 2.23 min LC/MS(ESI⁺) m/z; 370 [M + H]⁺ LC/MS (ESI⁻) m/z; 368 [M − H]⁻ 231 LC/MS:condition 3, retention time = 1.44 min LC/MS (ESI⁺) m/z; 402, 404 [M +H]⁺ LC/MS (ESI⁻) m/z; 400, 403 [M − H]⁻ 232 LC/MS: condition 3,retention time = 1.49 min LC/MS (ESI⁺) m/z; 390 [M + H]⁺ LC/MS (ESI⁻)m/z; 388 [M − H]⁻ 233 LC/MS: condition 3, retention time = 1.77 minLC/MS (ESI⁺) m/z; 495, 497, 499 [M + H]⁺ LC/MS (ESI⁻) m/z; 493, 495, 497[M − H]⁻ 234 LC/MS: condition 3, retention time = 1.20 min LC/MS (ESI⁺)m/z; 425 [M + H]⁺ LC/MS (ESI⁻) m/z; 423 [M − H]⁻ 235 LC/MS: condition 3,retention time = 2.44 min LC/MS (ESI⁺) m/z; 404, 406 [M + H]⁺ LC/MS(ESI⁻) m/z; 402, 404 [M − H]⁻ 236 LC/MS: condition 3, retention time =1.46 min LC/MS (ESI⁺) m/z; 353 [M + H]⁺ LC/MS (ESI⁻) m/z; 351 [M − H]⁻237 LC/MS: condition 3, retention time = 1.51 min LC/MS (ESI⁺) m/z; 417,419 [M + H]⁺ 238 LC/MS: condition 3, retention time = 1.55 min LC/MS(ESI⁺) m/z; 417, 419 [M + H]⁺ LC/MS (ESI⁻) m/z; 415, 417 [M − H]⁻ 239LC/MS: condition 3, retention time = 0.50 min LC/MS (ESI⁺) m/z; 334 [M +H]⁺ LC/MS (ESI⁻) m/z; 332 [M − H]⁻

TABLE^(a) 129 Ex Data 240 ¹H-NMR (DMSO-d₆) δ: 1.85-2.08 (m, 4H),2.20-2.34 (m, 2H), 2.96-3.09 (m, 2H), 3.09-3.22 (m, 1H), 3.74 (s, 2H),6.81 (d, J = 3.2 Hz, 1H), 7.48 (d, J = 3.2 Hz, 1H), 7.55 (s, 1H), 9.06(s, 1H), 9.52 (s, 1H), 12.52 (br s, 1H). LC/MS: condition 3, retentiontime = 0.88 min LC/MS (ESI⁺) m/z; 340 [M + H]⁺ 241 ¹H-NMR (DMSO-d₆) δ:1.95-2.08 (m, 4H), 2.22 (t, J = 11.1 Hz, 2H), 2.95 (d, J = 9.9 Hz, 2H),3.28 (s, 1H), 3.60 (s, 2H), 6.82 (br s, 1H), 7.28 (br s, 1H), 7.42 (d, J= 8.1 Hz, 2H), 7.49 (t, J = 2.7 Hz, 1H), 7.84 (d, J = 8.1 Hz, 2H), 7.91(br s, 1H), 9.51 (s, 1H), 12.52 (br s, 1H). LC/MS: condition 3,retention time = 0.73 min LC/MS (ESI⁺) m/z; 376 [M + H]⁺ LC/MS (ESI⁻)m/z; 374 [M − H]⁻ 242 ¹H-NMR (DMSO-d₆) δ: 1.95-2.04 (m, 4H), 2.28 (t, J= 10.1 Hz, 2H), 2.92 (d, J = 11.7 Hz, 2H), 3.16-3.19 (m, 1H), 3.70 (s,2H), 6.82 (dd, J = 3.3, 1.5 Hz, 1H), 7.49 (d, J = 3.3 Hz, 1H), 7.92 (d,J = 8.7 Hz, 1H), 8.11-8.13 (m, 2H), 9.51 (s, 1H). LC/MS: condition 3,retention time = 1.34 min LC/MS (ESI⁺) m/z; 383 [M + H]⁺ LC/MS (ESI⁻)m/z; 381 [M − H]⁻ 243 ¹H-NMR (DMSO-d₆) δ: 1.95-2.07 (m, 4H), 2.28 (t, J= 10.1 Hz, 2H), 2.94 (d, J = 11.1 Hz, 2H), 3.71 (s, 2H), 6.83 (dd, J =3.3, 1.2 Hz, 1H), 7.49 (d, J = 3.3 Hz, 1H), 7.97 (m, 2H), 8.13 (s, 1H),9.52 (s, 1H). LC/MS: condition 3, retention time = 1.65 min LC/MS (ESI⁺)m/z; 426 [M + H]⁺ LC/MS (ESI⁻) m/z; 424 [M − H]⁻ 244 ¹H-NMR (DMSO-d₆) δ:1.91-2.08 (m, 4H), 2.30 (td, J = 11.3, 2.9 Hz, 2H), 2.93 (d, J = 11.7Hz, 2H), 3.16-3.23 (m, 1H), 3.74 (s, 2H), 6.82 (d, J = 3.3 Hz, 1H), 7.48(d, J = 3.3 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.98 (s, 1H), 8.14 (d, J= 7.8 Hz, 1H), 9.50 (s, 1H). LC/MS: condition 3, retention time = 1.60min LC/MS (ESI⁺) m/z; 426 [M + H]⁺ LC/MS (ESI⁻) m/z; 424 [M − H]⁻ 245¹H-NMR (DMSO-d₆) δ: 1.35 (d, J = 6.6 Hz, 3H), 1.82-2.05 (m, 4H),2.05-2.30 (m, 2H), 2.83-2.95 (m, 1H), 3.02-3.19 (m, 1H), 3.55 (q, J =6.6 Hz, 1H), 6.79 (d, J = 8.3 Hz, 2H), 7.18-7.28 (m, 1H), 7.28-7.40 (m,4H), 7.48 (d, J = 3.3 Hz, 1H), 9.51 (s, 1H), 12.51 (br s, 1H). LC/MS:condition 3, retention time = 1.44 min LC/MS (ESI⁺) m/z; 347 [M + H]⁺LC/MS (ESI⁻) m/z; 345 [M − H]⁻ 246 LC/MS: condition 3, retention time =1.16 min LC/MS (ESI⁺) m/z; 282 [M + H]⁺ LC/MS (ESI⁻) m/z; 280 [M − H]⁻

TABLE^(a) 130 Ex Data 247 LC/MS: condition 3, retention time = 2.38 minLC/MS (ESI⁺) m/z; 406 [M + H]⁺ LC/MS (ESI⁻) m/z; 404 [M − H]⁻ 248 LC/MS:condition 3, retention time = 2.48 min LC/MS (ESI⁺) m/z; 422 [M + H]⁺LC/MS (ESI⁻) m/z; 420 [M − H]⁻ 249 LC/MS: condition 3, retention time =2.48 min LC/MS (ESI⁺) m/z; 383 [M + H]⁺ LC/MS (ESI⁻) m/z; 381 [M − H]⁻250 LC/MS: condition 3, retention time = 2.61 min LC/MS (ESI⁺) m/z; 401[M + H]⁺ LC/MS (ESI⁻) m/z; 399 [M − H]⁻ 251 LC/MS: condition 3,retention time = 2.67 min LC/MS (ESI⁺) m/z; 433 [M + H]⁺ LC/MS (ESI⁻)m/z; 431 [M − H]⁻ 252 LC/MS: condition 3, retention time = 2.36 minLC/MS (ESI⁺) m/z; 390 [M + H]⁺ LC/MS (ESI⁻) m/z; 388 [M − H]⁻ 253 LC/MS:condition 3, retention time = 0.65 min LC/MS (ESI⁺) m/z; 371 [M + H]⁺LC/MS (ESI⁻) m/z; 369 [M − H]⁻ 254 LC/MS: condition 3, retention time =1.24 min LC/MS (ESI⁺) m/z; 343 [M + H]⁺ 255 LC/MS: condition 3,retention time = 1.18 min LC/MS (ESI⁺) m/z; 335 [M + H]⁺ LC/MS (ESI⁻)m/z; 333 [M − H]⁻ 256 LC/MS: condition 3, retention time = 1.40 minLC/MS (ESI⁺) m/z; 367 [M + H]⁺ LC/MS (ESI⁻) m/z; 365 [M − H]⁻ 257 LC/MS:condition 3, retention time = 1.08 min LC/MS (ESI⁺) m/z; 327 [M + H]⁺258 LC/MS: condition 3, retention time = 1.48 min LC/MS (ESI⁺) m/z; 407[M + H]⁺ LC/MS (ESI⁻) m/z; 405 [M − H]⁻ 259 LC/MS: condition 3,retention time = 1.16 min LC/MS (ESI⁺) m/z; 310 [M + H]⁺ LC/MS (ESI⁻)m/z; 308 [M − H]⁻ 260 LC/MS: condition 3, retention time = 0.96 minLC/MS (ESI⁺) m/z; 354 [M + H]⁺ LC/MS (ESI⁻) m/z; 352 [M − H]⁻ 261 LC/MS:condition 3, retention time = 1.09 min LC/MS (ESI⁺) m/z; 382 [M + H]⁺262 LC/MS: condition 3, retention time = 2.22 min LC/MS (ESI⁺) m/z; 397[M + H]⁺ LC/MS (ESI⁻) m/z; 395 [M − H]⁻

TABLE^(a) 131 Ex Data 263 LC/MS: condition 3, retention time = 2.49 minLC/MS (ESI⁺) m/z; 406 [M + H]⁺ LC/MS (ESI⁻) m/z; 404 [M − H]⁻ 264 LC/MS:condition 3, retention time = 2.06 min LC/MS (ESI⁺) m/z; 386 [M + H]⁺LC/MS (ESI⁻) m/z; 384 [M − H]⁻ 265 LC/MS: condition 3, retention time =1.17 min LC/MS (ESI⁺) m/z; 355 [M + H]⁺ 266 LC/MS: condition 3,retention time = 1.17 min LC/MS (ESI⁺) m/z; 355 [M + H]⁺ 267 LC/MS:condition 3, retention time = 1.10 min LC/MS (ESI⁺) m/z; 341 [M + H]⁺268 LC/MS: condition 3, retention time = 1.51 min LC/MS (ESI⁺) m/z; 405[M + H]⁺ 269 LC/MS: condition 3, retention time = 1.51 min LC/MS (ESI⁺)m/z; 413 [M + H]⁺ LC/MS (ESI⁻) m/z; 411 [M − H]⁻ 270 ¹H-NMR (CD₃OD) δ:1.34 (m, 2H), 1.84-2.18 (m, 7H), 2.96 (d, J = 6.9 Hz, 2H), 3.23 (m, 1H),3.82 (s, 3H), 4.17 (s, 2H), 6.81 (d, J = 3.3 Hz, 1H), 7.01 (d, J = 8.7Hz, 2H), 7.40 (d, J = 3.3 Hz, 1H), 7.44 (d, J = 8.7 Hz, 2H) 9.30 (s,1H). LC/MS: condition 1, retention time = 2.72 min LC/MS (ESI⁺) m/z; 391[M + H]⁺ LC/MS (ESI⁻) m/z; 389 [M − H]⁻ 271 LC/MS: condition 1,retention time = 0.37 min LC/MS (ESI⁺) m/z; 355 [M + H]⁺ LC/MS (ESI⁻)m/z; 353 [M − H]⁻ 272 LC/MS: condition 1, retention time = 1.40 minLC/MS (ESI⁺) m/z; 315 [M + H]⁺ LC/MS (ESI⁻) m/z; 313 [M − H]⁻ 273 LC/MS:condition 1, retention time = 3.12 min LC/MS (ESI⁺) m/z; 418 [M + H]⁺LC/MS (ESI⁻) m/z; 416 [M − H]⁻ 274 LC/MS: condition 1, retention time =3.05 min LC/MS (ESI⁺) m/z; 418 [M + H]⁺ LC/MS (ESI⁻) m/z; 416 [M − H]⁻275 LC/MS: condition 1, retention time = 4.40 min LC/MS (ESI⁺) m/z; 427[M + H]⁺ LC/MS (ESI⁻) m/z; 425 [M − H]⁻ 276 LC/MS: condition 1,retention time = 2.59 min LC/MS (ESI⁺) m/z; 391 [M + H]⁺ LC/MS (ESI⁻)m/z; 389 [M − H]⁻ 277 LC/MS: condition 1, retention time = 2.52 minLC/MS (ESI⁺) m/z; 391 [M + H]⁺ LC/MS (ESI⁻) m/z; 389 [M − H]⁻

TABLE^(a) 132 Ex Data 278 LC/MS: condition 1, retention time = 0.37 minLC/MS (ESI⁺) m/z; 355 [M + H]⁺ LC/MS (ESI⁻) m/z; 353 [M − H]⁻ 279 LC/MS:condition 1, retention time = 0.39 min LC/MS (ESI⁺) m/z; 355 [M + H]⁺LC/MS (ESI⁻) m/z; 353 [M − H]⁻ 280 LC/MS: condition 1, retention time =0.63 min LC/MS (ESI⁺) m/z; 311 [M + H]⁺ LC/MS (ESI⁻) m/z; 309 [M − H]⁻281 LC/MS: condition 1, retention time = 0.39 min LC/MS (ESI⁺) m/z; 336[M + H]⁺ LC/MS (ESI⁻) m/z; 334 [M − H]⁻ 282 LC/MS: condition 1,retention time = 2.70 min LC/MS (ESI⁺) m/z; 400 [M + H]⁺ LC/MS (ESI⁻)m/z; 398 [M − H]⁻ 283 LC/MS: condition 3, retention time = 1.36 minLC/MS (ESI⁺) m/z; 325 [M + H]⁺ 284 LC/MS: condition 3, retention time =1.46 min LC/MS (ESI⁺) m/z; 339 [M + H]⁺ 285 LC/MS: condition 3,retention time = 1.36 min LC/MS (ESI⁺) m/z; 325 [M + H]⁺ 286 LC/MS:condition 3, retention time = 1.15 min LC/MS (ESI⁺) m/z; 311 [M + H]⁺287 LC/MS: condition 3, retention time = 1.22 min LC/MS (ESI⁺) m/z; 325[M + H]⁺ 288 LC/MS: condition 3, retention time = 1.07 min LC/MS (ESI⁺)m/z; 356 [M + H]⁺ LC/MS (ESI⁻) m/z; 354 [M − H]⁻ 289 LC/MS: condition 3,retention time = 1.33 min LC/MS (ESI⁺) m/z; 355 [M + H]⁺ 290 LC/MS:condition 3, retention time = 1.49 min LC/MS (ESI⁺) m/z; 339 [M + H]⁺LC/MS (ESI⁻) m/z; 337 [M − H]⁻ 291 LC/MS: condition 3, retention time =1.39 min LC/MS (ESI⁺) m/z; 325 [M + H]⁺ LC/MS (ESI⁻) m/z; 323 [M − H]⁻292 LC/MS: condition 3, retention time = 2.33 min LC/MS (ESI⁺) m/z; 379[M + H]⁺ LC/MS (ESI⁻) m/z; 377 [M − H]⁻ 293 LC/MS: condition 3,retention time = 1.37 min LC/MS (ESI⁺) m/z; 355 [M + H]⁺ LC/MS (ESI⁻)m/z; 353 [M − H]⁻ 294 LC/MS: condition 3, retention time = 1.09 minLC/MS (ESI⁺) m/z; 327 [M + H]⁺ LC/MS (ESI⁻) m/z; 325 [M − H]⁻

TABLE^(a) 133 Ex Data 295 LC/MS: condition 3, retention time = 1.36 minLC/MS (ESI⁺) m/z; 325 [M + H]⁺ 296 LC/MS: condition 3, retention time =1.10 min LC/MS (ESI⁺) m/z; 299 [M + H]⁺ 297 LC/MS: condition 3,retention time = 1.07 min LC/MS (ESI⁺) m/z; 329 [M + H]⁺ 298 LC/MS:condition 3, retention time = 1.03 min LC/MS (ESI⁺) m/z; 359 [M + H]⁺299 LC/MS: condition 3, retention time = 1.62 min LC/MS (ESI⁺) m/z; 440[M + H]⁺ 300 LC/MS: condition 3, retention time = 2.38 min LC/MS (ESI⁺)m/z; 400 [M + H]⁺ LC/MS (ESI⁻) m/z; 398 [M − H]⁻ 301 LC/MS: condition 3,retention time = 1.16 min LC/MS (ESI⁺) m/z; 350 [M + H]⁺ 302 LC/MS:condition 3, retention time = 1.14 min LC/MS (ESI⁺) m/z; 338 [M + H]⁺LC/MS (ESI⁻) m/z; 336 [M − H]⁻ 303 LC/MS: condition 3, retention time =1.31 min LC/MS (ESI⁺) m/z; 421 [M + H]⁺ 304 LC/MS: condition 3,retention time = 1.45 min LC/MS (ESI⁺) m/z; 421 [M + H]⁺ 305 LC/MS:condition 3, retention time = 1.20 min LC/MS (ESI⁺) m/z; 369 [M + H]⁺306 LC/MS: condition 3, retention time = 1.54 min LC/MS (ESI⁺) m/z; 397[M + H]⁺ 307 LC/MS: condition 3, retention time = 1.62 min LC/MS (ESI⁺)m/z; 440 [M + H]⁺ 308 LC/MS: condition 3, retention time = 1.74 minLC/MS (ESI⁺) m/z; 437 [M + H]⁺ LC/MS (ESI⁻) m/z; 435 [M − H]⁻ 309 LC/MS:condition 3, retention time = 2.00 min LC/MS (ESI⁺) m/z; 533 [M + H]⁺LC/MS (ESI⁻) m/z; 531 [M − H]⁻ 310 LC/MS: condition 3, retention time =1.71 min LC/MS (ESI⁺) m/z; 440 [M + H]⁺ 311 LC/MS: condition 3,retention time = 1.30 min LC/MS (ESI⁺) m/z; 397 [M + H]⁺ 312 LC/MS:condition 3, retention time = 1.46 min LC/MS (ESI⁺) m/z; 383 [M + H]⁺LC/MS (ESI⁻) m/z; 381 [M − H]⁻ 313 LC/MS: condition 3, retention time =1.46 min LC/MS (ESI⁺) m/z; 383 [M + H]⁺ 314 LC/MS: condition 3,retention time = 1.23 min LC/MS (ESI⁺) m/z; 393 [M + H]⁺

TABLE^(a) 134 Ex Data 315 LC/MS: condition 3, retention time = 0.96 minLC/MS (ESI⁺) m/z; 384 [M + H]⁺ 316 LC/MS: condition 3, retention time =1.41 min LC/MS (ESI⁺) m/z; 337 [M + H]⁺ 317 LC/MS: condition 3,retention time = 2.52 min LC/MS (ESI⁺) m/z; 421 [M + H]⁺ LC/MS (ESI⁻)m/z; 419 [M − H]⁻ 318 LC/MS: condition 3, retention time = 1.13 minLC/MS (ESI⁺) m/z; 382 [M + H]⁺ 319 LC/MS: condition 3, retention time =1.13 min LC/MS (ESI⁺) m/z; 382 [M + H]⁺ 320 LC/MS: condition 3,retention time = 1.41 min LC/MS (ESI⁺) m/z; 436 [M + H]⁺ LC/MS (ESI⁻)m/z; 434 [M − H]⁻ 321 LC/MS: condition 3, retention time = 1.41 minLC/MS (ESI⁺) m/z; 436 [M + H]⁺ LC/MS (ESI⁻) m/z; 434 [M − H]⁻ 322 LC/MS:condition 3, retention time = 1.60 min LC/MS (ESI⁺) m/z; 421 [M + H]⁺LC/MS (ESI⁻) m/z; 419 [M − H]⁻ 323 LC/MS: condition 3, retention time =1.76 min LC/MS (ESI⁺) m/z; 405 [M + H]⁺ 324 LC/MS: condition 3,retention time = 1.83 min LC/MS (ESI⁺) m/z; 419 [M + H]⁺ 325 LC/MS:condition 3, retention time = 1.23 min LC/MS (ESI⁺) m/z; 343 [M + H]⁺326 LC/MS: condition 3, retention time = 1.38 min LC/MS (ESI⁺) m/z; 387[M + H]⁺ 327 LC/MS: condition 3, retention time = 1.19 min LC/MS (ESI⁺)m/z; 341 [M + H]⁺ 328 LC/MS: condition 3, retention time = 1.26 minLC/MS (ESI⁺) m/z; 361 [M + H]⁺ LC/MS (ESI⁻) m/z; 359 [M − H]⁻ 329 LC/MS:condition 3, retention time = 1.08 min LC/MS (ESI⁺) m/z; 285 [M + H]⁺LC/MS (ESI⁻) m/z; 283 [M − H]⁻ 330 LC/MS: condition 3, retention time =1.18 min LC/MS (ESI⁺) m/z; 299 [M + H]⁺ 331 LC/MS: condition 3,retention time = 1.28 min LC/MS (ESI⁺) m/z; 313 [M + H]⁺ 332 LC/MS:condition 3, retention time = 1.38 min LC/MS (ESI⁺) m/z; 327 [M + H]⁺333 LC/MS: condition 3, retention time = 1.21 min LC/MS (ESI⁺) m/z; 309[M + H]⁺ 334 LC/MS: condition 1, retention time = 0.34 min LC/MS (ESI⁺)m/z; 424 [M + H]⁺ LC/MS (ESI⁻) m/z; 422 [M − H]⁻

TABLE^(a) 135 Ex Data 335 LC/MS: condition 1, retention time = 2.94 minLC/MS (ESI⁺) m/z; 468 [M + H]⁺ LC/MS (ESI⁻) m/z; 466 [M − H]⁻ 336 LC/MS:condition 1, retention time = 2.75 min LC/MS (ESI⁺) m/z; 468 [M + H]⁺LC/MS (ESI⁻) m/z; 466 [M − H]⁻ 337 LC/MS: condition 1, retention time =2.77 min LC/MS (ESI⁺) m/z; 440 [M + H]⁺ LC/MS (ESI⁻) m/z; 438 [M − H]⁻338 LC/MS: condition 3, retention time = 1.15 min LC/MS (ESI⁺) m/z; 329[M + H]⁺ LC/MS (ESI⁻) m/z; 327 [M − H]⁻ 339 LC/MS: condition 3,retention time = 1.19 min LC/MS (ESI⁺) m/z; 347 [M + H]⁺ LC/MS (ESI⁻)m/z; 345 [M − H]⁻ 340 LC/MS: condition 3, retention time = 0.81 minLC/MS (ESI⁺) m/z; 368 [M + H]⁺ 341 LC/MS: condition 3, retention time =1.39 min LC/MS (ESI⁺) m/z; 410 [M + H]⁺ LC/MS (ESI⁻) m/z; 408 [M − H]⁻342 LC/MS: condition 3, retention time = 1.85 min LC/MS (ESI⁺) m/z; 403[M + H]⁺ LC/MS (ESI⁻) m/z; 401 [M − H]⁻ 343 LC/MS: condition 3,retention time = 1.38 min LC/MS (ESI⁺) m/z; 383 [M + H]⁺ LC/MS (ESI⁻)m/z; 381 [M − H]⁻ 344 LC/MS: condition 3, retention time = 1.31 minLC/MS (ESI⁺) m/z; 343 [M + H]⁺ LC/MS (ESI⁻) m/z; 341 [M − H]⁻ 345 LC/MS:condition 3, retention time = 1.31 min LC/MS (ESI⁺) m/z; 432 [M + H]⁺LC/MS (ESI⁻) m/z; 430 [M − H]⁻ 346 ¹H-NMR (CD₃OD) δ: 1.39-1.74 (m, 6H),1.95 (m, 2H), 2.19 (tt, J = 11.7, 3.3, 1H), 3.05 (tt, J = 12.6, 3.9,1H), 3.67 (d, J = 14.4 Hz, 1H), 4.02 (d, J = 14.4 Hz, 1H), 6.70 (d, J =3.3 Hz, 1H), 7.28 (m, 4H), 7.50 (m, 2H), 9.17 (s, 1H). LC/MS: condition1, retention time = 3.77 min LC/MS (ESI⁺) m/z; 473 [M + H]⁺ LC/MS (ESI⁻)m/z; 389 [M − H]⁻ 347 ¹H-NMR (CD₃OD) δ: 1.41-1.76 (m, 6H), 1.96 (m, 2H),2.20 (tt, J = 12, 3.3, 1H), 3.06 (tt, J = 11.7, 3.6, 1H), 3.65 (d, J =14.4 Hz, 1H), 4.02 (d, J = 14.4 Hz, 1H), 6.70 (d, J = 3.3 Hz, 1H), 7.02(t, J = 8.7 Hz, 2H), 7.28 (d, J = 3.3 Hz, 1H), 7.53 (dd, J = 8.7, 5.4Hz, 2H), 9.17 (s, 1H). LC/MS: condition 1, retention time = 3.84 minLC/MS (ESI⁺) m/z; 491 [M + H]⁺ LC/MS (ESI⁻) m/z; 489 [M − H]⁻

TABLE^(a) 136 Ex Data 348 ¹H-NMR (DMSO-d₆) δ: 1.56-1.85 (m, 4H), 1.92(dd, J = 12.7, 2.5 Hz, 2H), 2.03 (dd, J = 13.1, 3.3 Hz, 2H), 2.28 (tt, J= 11.4, 3.3 Hz, 1H), 3.16 (tt, J = 11.9, 3.7 Hz, 1H), 6.69 (br s, 1H),6.82-6.85 (m, 1H), 7.24 (br s, 1H), 7.49 (t, J = 2.9 Hz, 1H), 9.51 (s,1H), 12.52 (br s, 1H). LC/MS: condition 1, retention time = 1.22 minLC/MS (ESI⁺) m/z; 285 [M + H]⁺ LC/MS (ESI⁻) m/z; 283 [M − H]⁻ 349 LC/MS:condition 1, retention time = 3.42 min LC/MS (ESI⁺) m/z; 379 [M + H]⁺LC/MS (ESI⁻) m/z; 377 [M − H]⁻ 350 ¹H-NMR (DMSO-d₆) δ: 1.67-1.87 (m,4H), 1.91-2.10 (m, 4H), 2.35-2.43 (m, 1H), 3.14-3.25 (m, 1H), 4.37 (d, J= 5.7 Hz, 2H), 6.84-6.87 (m, 1H), 7.44 (d, J = 7.8 Hz, 2H), 7.49 (t, J =2.9 Hz, 1H), 7.80 (d, J = 7.8 Hz, 2H), 8.45 (t, J = 5.7 Hz, 1H), 9.51(s, 1H), 12.52 (br s, 1H). LC/MS: condition 1, retention time = 3.34 minLC/MS (ESI⁺) m/z; 400 [M + H]⁺ LC/MS (ESI⁻) m/z; 398 [M − H]⁻ 351 ¹H-NMR(DMSO-d₆) δ: 1.65-1.83 (m, 4H), 1.88-2.11 (m, 5H), 3.14-3.26 (m, 1H),6.19 (d, J = 7.8 Hz, 1H), 6.84-6.87 (m, 1H), 7.46-7.51 (m, 6H), 9.14 (d,J = 7.8 Hz, 1H), 9.51 (s, 1H), 12.52 (br s, 1H). LC/MS: condition 1,retention time = 3.34 min LC/MS (ESI⁺) m/z; 400 [M + H]⁺ LC/MS (ESI⁻)m/z; 398 [M − H]⁻ 352 ¹H-NMR (DMSO-d₆) δ: 1.60-1.88 (m, 6H), 1.98-2.06(m, 2H), 2.19-2.32 (m, 1H), 2.69-2.76 (m, 2H), 3.12-3.22 (m, 1H),3.25-3.33 (m, 2H), 6.83-6.86 (m, 1H), 7.24 (d, J = 8.3 Hz, 2H), 7.35 (d,J = 8.9 Hz, 2H), 7.50 (t, J = 2.6 Hz, 1H), 7.85 (t, J = 5.6 Hz, 1H), 9.52 (s, 1H), 12.53 (br s, 1H). LC/MS: condition 1, retention time =3.84 min LC/MS (ESI⁺) m/z; 423 [M + H]⁺ LC/MS (ESI⁻) m/z; 421 [M − H]⁻353 ¹H-NMR (DMSO-d₆) δ: 1.55-1.89 (m, 6H), 1.97-2.05 (m, 2H), 2.26-2.39(m, 1H), 3.11-3.22 (m, 1H), 3.26-3.34 (m, 2H), 4.58-4.66 (m, 1H), 5.45(d, J = 4.5 Hz, 1H), 6.84 (d, J = 3.3 Hz, 1H), 7.21-7.28 (m, 1H), 7.33(d, J = 4.1 Hz, 4H), 7.49 (d, J = 3.3 Hz, 1H), 7.81 (t, J = 5.3 Hz, 1H),9.51 (s, 1H), 12.52 (br s, 1H). LC/MS: condition 1, retention time =3.19 min LC/MS (ESI⁺) m/z; 405 [M + H]⁺ LC/MS (ESI⁻) m/z; 403 [M − H]⁻

TABLE^(a) 137 Ex Data 354 ¹H-NMR (DMSO-d₆) δ: 1.65-1.82 (m, 4H),1.87-1.95 (m, 2H), 2.00-2.09 (m, 2H), 2.36-2.43 (m, 1H), 3.13-3.24 (m,1H), 3.85-3.98 (m, 2H), 6.84-6.87 (m, 1H), 7.49 (t, J = 2.9 Hz, 1H),8.47 (t, J = 6.5 Hz, 1H), 9.51 (s, 1H), 12.52 (br s, 1H). LC/MS:condition 1, retention time = 3.27 min LC/MS (ESI⁺) m/z; 367 [M + H]⁺LC/MS (ESI⁻) m/z; 365 [M − H]⁻ 355 ¹H-NMR (DMSO-d₆) δ: 1.64-1.82 (m,4H), 1.87-1.96 (m, 2H), 2.01-2.09 (m, 2H), 2.26-2.39 (m, 1H), 3.14-3.25(m, 1H), 4.15 (d, J = 5.9 Hz, 2H), 6.85-6.88 (m, 1H), 7.50 (t, J = 2.6Hz, 1H), 8.55 (t, J = 5.3 Hz, 1H), 9.52 (s, 1H), 12.53 (br s, 1H).LC/MS: condition 1, retention time = 2.65 min LC/MS (ESI⁺) m/z; 324 [M +H]⁺ LC/MS (ESI⁻) m/z; 322 [M − H]⁻ 356 ¹H-NMR (DMSO-d₆) δ: 1.64-1.82 (m,4H), 1.87-1.95 (m, 2H), 2.00-2.08 (m, 2H), 2.26-2.37 (m, 1H), 2.66 (t, J= 6.6 Hz, 2H), 3.13-3.24 (m, 1H), 3.26-3.32 (m, 2H), 6.84-6.87 (m, 1H),1 7.50 (t, J = 3.3 Hz, H), 8.19 (t, J = 5.6 Hz, 1H), 9.52 (s, 1H), 12.53(br s, 1H). LC/MS: condition 1, retention time = 2.65 min LC/MS (ESI⁺)m/z; 338 [M + H]⁺ LC/MS (ESI⁻) m/z; 336 [M − H]⁻ 357 LC/MS: condition 1,retention time = 2.90 min LC/MS (ESI⁺) m/z; 364 [M + H]⁺ LC/MS (ESI⁻)m/z; 362 [M − H]⁻ 358 LC/MS: condition 1, retention time = 2.47 minLC/MS (ESI⁺) m/z; 355 [M + H]⁺ LC/MS (ESI⁻) m/z; 353 [M − H]⁻ 359 ¹H-NMR(DMSO-d₆) δ: 0.39 (dd, J = 4.3, 2.6 Hz, 2H), 0.61 (dd, J = 6.9, 2.3 Hz,2H), 1.61-1.78 (m, 4H), 1.80-1.89 (m, 2H), 1.98-2.07 (m, 2H), 2.16-2.28(m, 1H), 2.60-2.68 (m, 1H), 3.11-3.22 (m, 1H), 6.84 (dd, J = 3.3, 2.0Hz, 1H), 7.50 (t, J = 3.0 Hz, 1H), 7.83 (d, J = 4.3 Hz, 1H), 9.52 (s,1H), 12.53 (br s, 1H). LC/MS: condition 1, retention time = 2.92 minLC/MS (ESI⁺) m/z; 325 [M + H]⁺ LC/MS (ESI⁻) m/z; 323 [M − H]⁻ 360 ¹H-NMR(DMSO-d₆) δ: 1.62-1.80 (m, 4H), 1.83-1.92 (m, 2H), 1.99-2.07 (m, 2H),2.26-2.37 (m, 1H), 3.10-3.19 (m, 1H), 3.32-3.44 (m, 4H), 4.65 (t, J =5.6 Hz, 1H), 6.83-6.87 (m, 1H), 7.48-7.52 (m, 1H), 7.76 (t, J = 5.9 Hz,1H), 9.52 (s, 1H), 12.53 (br s, 1H). LC/MS: condition 1, retention time= 2.34 min LC/MS (ESI⁺) m/z; 329 [M + H]⁺ LC/MS (ESI⁻) m/z; 327 [M − H]⁻

TABLE^(a) 138 Ex Data 361 ¹H-NMR (DMSO-d₆) δ: 1.55-1.70 (m, 2H),1.76-1.87 (m, 4H), 1.97-2.06 (m, 2H), 2.32-2.46 (m, 1H), 3.12-3.23 (m,1H), 3.58 (dd, J = 10.2, 3.6 Hz, 1H), 3.89-3.96 (m, 1H), 3.99-4.07 (m,1H), 4.41-4.49 (m, 1H), 5.68-5.73 (m, 1H), 6.88 (dd, J = 3.3, 2.0 Hz,2H), 7.49 (t, J = 3.0 Hz, 1H), 9.51 (s, 1H), 12.52 (br s, 1H). LC/MS:condition 1, retention time = 1.79 min LC/MS (ESI⁺) m/z; 341 [M − H]⁺LC/MS (ESI⁻) m/z; 339 [M − H]⁻ 362 ¹H-NMR (DMSO-d₆) δ: 1.59-1.86 (m,6H), 1.98-2.06 (m, 3H), 2.19-2.30 (m, 2H), 2.83 (t, J = 7.3 Hz, 2H),3.15-3.25 (m, 1H), 6.83-6.86 (m, 1H), 7.43 (d, J = 7.9 Hz, 2H), 7.50 (t,J = 3.0 Hz, 1H), 7.78 (d, J = 7.6 Hz, 2H), 7.87 (t, J = 5.6 Hz, 1H),9.52 (s, 1H), 12.53 (br s, 1H). LC/MS: condition 1, retention time =3.40 min LC/MS (ESI⁺) m/z; 414 [M + H]⁺ LC/MS (ESI⁻) m/z; 412 [M − H]⁻363 ¹H-NMR (DMSO-d₆) δ: 1.56-1.70 (m, 2H), 1.73-1.91 (m, 4H), 1.97-2.06(m, 2H), 2.33-2.44 (m, 1H), 3.13-3.25 (m, 1H), 3.74-3.86 (m, 1H),3.97-4.05 (m, 1H), 4.11-4.20 (m, 1H), 4.41-4.56 (m, 2H), 6.89 (dd, J =3.3, 2.0 Hz, 1H), 7.49 (t, J = 2.6 Hz, 1H), 9.51 (s, 1H), 12.52 (br s,1H). LC/MS: condition 1, retention time = 2.88 min LC/MS (ESI⁺) m/z; 350[M + H]⁺ LC/MS (ESI⁻) m/z; 348 [M − H]⁻ 364 ¹H-NMR (CDCl₃) δ: 1.30-1.40(m, 2H), 1.81-2.02 (m, 2H), 2.05-2.25 (m, 5H), 3.10 (d, J = 6.0 Hz, 2H),3.12-3.21 (m, 1H), 6.76 (dd, J = 3.6, 2.1 Hz, 1H), 7.29 (t, J = 3.0 Hz,1H), 7.55-7.73 (m, 3H), 7.91-7.99 (m, 2H), 9.00 (br s, 1H), 9.21 (s,1H). LC/MS: condition 3, retention time = 2.00 min LC/MS (ESI⁺) m/z; 396[M + H]⁺ LC/MS (ESI⁻) m/z; 394 [M − H]⁻ 365 ¹H-NMR (CDCl₃) δ: 1.31-1.56(m, 2H), 1.86-2.02 (m, 2H), 2.06-2.24 (m, 5H), 3.09 (d, J = 6.0 Hz, 2H),3.11-3.22 (m, 1H), 6.76 (dd, J = 6.0, 2.4 Hz, 1H), 7.22-7.31 (m, 3H),7.93-8.00 (m, 2H), 9.13 (br s, 1H), 9.21 (s, 1H). LC/MS: condition 3,retention time = 2.06 min LC/MS (ESI⁺) m/z; 414 [M + H]⁺ LC/MS (ESI⁻)m/z; 412 [M − H]⁻ 366 ¹H-NMR (DMSO-d₆) δ: 0.96-1.07 (m, 4H), 1.31-1.51(m, 2H), 1.70-1.91 (m, 2H), 1.95-2.18 (m, 4H), 2.69-2.84 (m, 1H), 3.15(d, J = 5.7 Hz, 2H), 3.65 (s, 2H), 6.81 (dd, J = 3.3, 1.8 Hz, 1H), 7.49(t, J = 2.7 Hz, 1H), 9.51 (s, 1H), 12.52 (br s, 1H). LC/MS: condition 3,retention time = 1.51 min LC/MS (ESI⁺) m/z; 360 [M + H]⁺ LC/MS (ESI⁻)m/z; 358 [M − H]⁻

TABLE^(a) 139 Ex Data 367 ¹H-NMR (CDCl₃) δ: 1.20-1.38 (m, 2H), 1.58-1.67(m, 1H), 1.87-2.05 (m, 2H), 2.06-2.21 (m, 4H), 3.09-3.19 (m, 1H), 3.22(d, J = 6.0 Hz, 2H), 6.78 (dd, J = 3.0, 1.8 Hz, 1H), 7.29 (t, J = 3.0Hz, 1H), 9.11 (br s, 1H), 9.22 (s, 1H). LC/MS: condition 3, retentiontime = 2.42 min LC/MS (ESI⁺) m/z; 382 [M + H]⁺ 368 ¹H-NMR (CDCl₃) δ:1.51-1.56 (m, 2H), 1.92-2.12 (m, 2H), 2.13-2.32 (m, 4H), 2.33-2.51 (m,1H), 3.11-3.20 (m, 1H), 3.21 (d, J = 6.6 Hz, 2H), 6.77 (dd, J = 6.0, 2.1Hz, 1H), 7.30 (t, J = 6.0 Hz, 1H), 9.11 (br s, 1H), 9.22 (s, 1H). LC/MS:condition 3, retention time = 2.16 min LC/MS (ESI⁺) m/z; 388 [M + H]⁺LC/MS (ESI⁻) m/z; 386 [M − H]⁻ 369 ¹H-NMR (CDCl₃) δ: 1.20-1.38 (m, 2H),1.70-1.85 (m, 1H), 1.85-2.08 (m, 4H), 2.11-2.22 (m, 2H), 3.10-3.22 (m,1H), 3.26 (d, J = 6.6 Hz, 2H), 6.78 (dd, J = 3.3, 2.4 Hz, 1H), 7.29 (t,J = 2.7 Hz, 1H), 9.14 (br s, 1H), 9.22 (s, 1H). LC/MS: condition 3,retention time = 2.09 min LC/MS (ESI⁺) m/z; 297 [M + H]⁺ LC/MS(ESI⁻)m/z; 295 [M − H]⁻ 370 ¹H-NMR (DMSO-d₆) δ: 1.22-1.40 (m, 2H), 1.47 (s,6H), 1.64-1.83 (m, 3H), 1.91-2.09 (m, 3H), 2.41-2.57 (m, 1H), 3.21-3.36(m, 1H), 3.30 (br s, 1H), 4.26 (d, J = 6.9 Hz, 1H), 5.07 (s, 1H),6.85-6.90 (m, 1H), 7.42-7.52 (m, 1H), 7.89 (s, 1H), 9.52 (s, 1H), 12.53(s, 1H). LC/MS: condition 3, retention time = 1.53 min LC/MS (ESI⁺) m/z;381 [M + H]⁺ LC/MS (ESI⁻) m/z; 379 [M − H]⁻ 371 ¹H-NMR (DMSO-d₆) δ:1.06-1.24 (m, 2H), 1.29-1.45 (m, 1H), 1.66-1.84 (m, 2H), 1.87-2.07 (m,4H), 2.40-2.54 (m, 2H), 3.05-3.20 (m, 1H), 3.30 (br s, 1H), 6.79 (d, J =3.3 Hz, 1H), 7.48 (d, J = 3.3 Hz, 1H), 9.50 (s, 1H). LC/MS: condition 3,retention time = 0.99 min LC/MS (ESI⁺) m/z; 271 [M + H]⁺ 372 ¹H-NMR(DMSO-d₆) δ: 1.12-1.31 (m, 2H), 1.52-1.63 (m, 1H), 1.64-1.82 (m, 2H),1.82-2.07 (m, 4H), 3.04 (t, J = 6.6 Hz, 2H), 3.08-3.20 (m, 1H), 3.65 (s,2H), 6.80 (dd, J = 3.0, 1.8 Hz, 1H), 7.48 (t, J = 3.0 Hz, 1H), 8.19-8.28(m, 1H), 9.51 (s, 1H), 12.51 (br s, 1H). LC/MS: condition 3, retentiontime = 1.51 min LC/MS (ESI⁺) m/z; 338 [M + H]⁺ LC/MS (ESI⁻) m/z; 336 [M− H]⁻ 373 ¹H-NMR (DMSO-d₆) δ: 1.12-1.32 (m, 2H), 1.46-1.64 (m, 1H),1.65-1.82 (m, 2H), 1.82-2.07 (m, 4H), 3.05 (t, J = 6.0 Hz, 2H),3.07-3.20 (m, 1H), 3.23 (d, J = 11.6 Hz, 1H), 3.27-3.35 (m, 1H), 6.79(dd, J = 3.0, 1.8 Hz, 1H), 7.48 (t, J = 3.0 Hz, 1H), 8.18-8.31 (m, 1H),9.51 (s, 1H), 12.51 (br s, 1H). LC/MS: condition 3, retention time =1.75 min LC/MS (ESI⁺) m/z; 381 [M + H]⁺ LC/MS (ESI⁻) m/z; 379 [M − H]⁻

TABLE^(a) 140 Ex Data 374 ¹H-NMR (DMSO-d₆) δ: 1.85-2.02 (m, 4H),2.13-2.30 (m, 2H), 2.36 (s, 3H), 2.86-2.99 (m, 2H), 3.10-3.24 (m, 1H),3.67 (s, 2H), 5.09 (q, J = 9.0 Hz, 2H), 6.81 (d, J = 3.3 Hz, 1H), 7.49(d, J = 3.3 Hz, 1H), 9.52 (s, 1H), 12.54 (br s, 1H). LC/MS: condition 3,retention time = 1.50 min LC/MS (ESI⁺) m/z; 381 [M + H]⁺ LC/MS (ESI⁻)m/z; 379 [M − H]⁻ 375 ¹H-NMR (DMSO-d₆) δ: 1.86-2.04 (m, 4H), 2.16-2.32(m, 2H), 2.62 (t, J = 7.5 Hz, 2H), 2.89 (t, J = 7.5 Hz, 2H), 3.01-3.12(m, 2H), 3.12-3.24 (m, 1H), 6.76 (d, J = 3.3 Hz, 1H), 7.47 (d, J = 3.3Hz, 1H), 7.49 (d, J = 7.8 Hz, 2H), 7.76 (d, J = 7.8 Hz, 2H), 9.52 (s,1H), 12.53 (br s, 1H). LC/MS: condition 3, retention time = 1.38 minLC/MS (ESI⁺) m/z; 372 [M + H]⁺ LC/MS (ESI⁻) m/z; 370 [M − H]⁻ 376 ¹H-NMR(CDCl₃) δ: 2.19-2.28 (m, 4H), 3.14-3.23 (m, 2H), 3.46-3.53 (m, 1H), 4.06(d, J = 12.6 Hz, 2H), 6.67 (dd, J = 3.3, 2.4 Hz, 1H), 6.96 (d, J = 9.0Hz, 2H), 7.53 (d, J = 9.0 Hz, 2H), 9.06 (br s, 1H), 9.24 (s, 1H). LC/MS:condition 3, retention time = 2.07 min LC/MS (ESI⁺) m/z; 344 [M + H]⁺LC/MS (ESI⁻) m/z; 342 [M − H]⁻ 377 ¹H-NMR (DMSO-d₆) δ: 1.90-2.08 (m,4H), 2.11-2.30 (m, 2H), 2.70-2.76 (m, 1H), 2.87-3.01 (m, 2H), 3.62 (s,2H), 7.56 (d, J = 8.3 Hz, 2H), 7.66 (s, 1H), 7.80 (d, J = 3.3 Hz, 2H),9.51 (s, 1H), 12.51 (br s, 1H). LC/MS: condition 3, retention time =1.45 min LC/MS (ESI⁺) m/z; 392, 394 [M + H]⁺ LC/MS (ESI⁻) m/z; 390, 392[M − H]⁻ 378 ¹H-NMR (CDCl₃) δ: 1.56 (m, 2H), 1.94-2.07 (m, 8H),2.20-2.33 (m, 6H), 3.01-3.26 (m, 7H), 3.41 (m, 1H), 4.26 (d, J = 5.4 Hz,1H), 4.34 (d, J = 5.4 Hz, 1H), 4.44 (m, 2H), 6.77 (m, 1H), 6.80 (m, 1H),7.22-7.32 (m, 10H), 9.22 (s, 2H), 10.04 (br s, 2H). LC/MS: condition 1,retention time = 0.99, 1.25 min (cis/trans mixture) LC/MS (ESI⁺) m/z;389 [M + H]⁺ LC/MS (ESI⁻) m/z; 387 [M − H]⁻ 379 ¹H-NMR (CDCl₃) δ: 1.57(m, 2H), 1.94-2.07 (m, 8H), 2.19-2.32 (m, 6H), 3.01-3.22 (m, 7H), 3.41(m, 1H), 4.27 (d, J = 5.4 Hz, 1H), 4.34 (d, J = 5.4 Hz, 1H), 4.44 (m,2H), 6.76 (m, 1H), 6.80 (m, 1H), 7.22-7.30 (m, 10H), 9.22 (s, 2H), 10.28(br s, 2H). LC/MS: condition 1, retention time = 0.87, 1.03 min(cis/trans mixture) LC/MS (ESI⁺) m/z; 389 [M + H]⁺ LC/MS (ESI⁻) m/z; 387[M − H]⁻

TABLE^(a) 141 Ex Data 380 ¹H-NMR (DMSO-d₆) δ: 1.58 (m, 6H), 1.75-1.84(m, 12H), 2.02 (m, 4H), 2.17 (m, 2H), 2.60 (m, 12H), 2.75 (m, 3H), 2.82(m, 12H), 3.17 (m, 2H), 3.51 (m, 1H), 6.82 (m, 1H), 6.88 (m, 2H), 7.48(m, 3H), 9.50 (s, 2H), 9.52 (s, 1H). LC/MS: condition 1, retention time= 2.75 min LC/MS (ESI⁺) m/z; 363 [M + H]⁺ LC/MS (ESI⁻) m/z; 361 [M − H]⁻381a ¹H-NMR (DMSO-d₆) δ: 1.76-1.96 (m, 6H), 2.10-2.23 (m, 2H), 3.30-3.40(m, 1H), 3.49-3.57 (m, 1H), 5.57 (d, J = 6.9 Hz, 1H), 6.61-6.68 (m, 2H),6.86-6.94 (m, 3H), 7.50 (t, J = 2.6 Hz, 1H), 9.53 (s, 1H), 12.53 (br s,1H). LC/MS: condition 1, retention time = 3.22 min LC/MS (ESI⁺) m/z; 351[M + H]⁺ LC/MS (ESI⁻) m/z; 349 [M − H]⁻ 381b ¹H-NMR (DMSO-d₆) δ: 1.41(qd, J = 12.9, 3.6 Hz, 2H), 1.84-2.19 (m, 6H), 3.20 (tt, J = 11.9, 3.6Hz, 1H), 3.31-3.39 (m, 1H), 5.37 (d, J = 8.3 Hz, 1H), 6.60-6.66 (m, 2H),6.86-6.95 (m, 3H), 7.50 (d, J = 3.3 Hz, 1H), 9.53 (s, 1H), 12.54 (br s,1H). LC/MS: condition 1, retention time = 2.82 min LC/MS (ESI⁺) m/z; 351[M + H]⁺ LC/MS (ESI⁻) m/z; 349 [M − H]⁻ 382a LC/MS: condition 3,retention time = 1.51 min LC/MS (ESI⁺) m/z; 392, 399 [M + H]⁺ LC/MS(ESI⁻) m/z; 390, 397 [M − H]⁻ 382b ¹H-NMR (CDCl₃) δ: 1.26-1.46 (m, 2H),1.87-2.05 (m, 2H), 2.08-2.23 (m, 4H), 2.76-2.91 (m, 1H), 3.10-3.24 (m,1H), 3.44 (d, J = 12.5 Hz, 1H), 3.48 (d, J = 12.5 Hz, 1H), 6.76 (dd, J =3.3, 1.8 Hz, 1H), 7.29 (t, J = 3.3 Hz, 1H), 9.08 (br s, 1H), 9.21 (s,1H). LC/MS: condition 3, retention time = 1.28 min LC/MS (ESI⁺) m/z; 399[M + H]⁺ LC/MS (ESI⁻) m/z; 397 [M − H]⁻ 383a ¹H-NMR (DMSO-d₆) δ:1.60-1.75 (m, 4H), 1.77-1.88 (m, 2H), 2.12-2.25 (m, 1H), 2.25-2.37 (m,1H), 2.85-2.92 (m, 1H), 3.20-3.40 (m, 3H), 6.98 (dd, J = 3.3, 2.0 Hz,1H), 7.45 (t, J = 2.6 Hz, 1H), 9.52 (s, 1H), 12.51 (br s, 1H). LC/MS:condition 1, retention time = 2.90 min LC/MS (ESI⁺) m/z; 389 [M + H]⁺LC/MS (ESI⁻) m/z; 387 [M − H]⁻ 383b ¹H-NMR (DMSO-d₆) δ: 1.23-1.39 (m,2H), 1.70-1.86 (m, 2H), 1.96-2.09 (m, 4H), 2.17-2.28 (m, 1H), 2.54-2.65(m, 1H), 3.14 (tt, J = 12.2, 3.0 Hz, 1H), 3.33-3.45 (m, 2H), 6.82 (d, J= 2.6 Hz, 1H), 7.49 (d, J = 2.6 Hz, 1H), 9.52 (s, 1H), 12.53 (br s, 1H).LC/MS: condition 1, retention time = 1.84 min LC/MS (ESI⁺) m/z; 389 [M +H]⁺ LC/MS (ESI⁻) m/z; 387 [M − H]⁻

TABLE^(a) 142 Ex Data 384a ¹H-NMR (DMSO-d₆) δ: 1.58-1.86 (m, 6H),2.09-2.30 (m, 2H), 2.41-2.54 (m, 1H), 2.69-2.81 (m, 1H), 3.25 (s, 2H),3.88-4.05 (m, 2H), 6.94-6.98 (m, 1H), 7.44 (t, J = 3.0 Hz, 1H),8.32-8.45 (m, 1H), 9.51 (s, 1H), 12.49 (s, 1H). LC/MS: condition 3,retention time = 1.35 min LC/MS (ESI⁺) m/z; 396 [M + H]⁺ LC/MS (ESI⁻)m/z; 394 [M − H]⁻ 384b ¹H-NMR (DMSO-d₆) δ: 1.25-1.41 (m, 2H), 1.67-1.84(m, 2H), 1.94-2.05 (m, 4H), 2.44-2.57 (m, 1H), 3.06-3.20 (m, 1H), 3.26(s, 2H), 3.87-4.02 (m, 2H), 6.78 (dd, J = 3.0, 1.5 Hz, 1H), 7.48 (t, J =3.0 Hz, 1H), 8.41 (br s, 1H), 9.50 (s, 1H), 12.51 (s, 1 H). LC/MS:condition 3, retention time = 1.22 min LC/MS (ESI⁺) m/z; 396 [M + H]⁺LC/MS (ESI⁻) m/z; 394 [M − H]⁻ 385b ¹H-NMR (CD₃OD) δ: 1.35 (m, 2H), 1.84(m, 2H), 2.07 (m, 4H), 2.58 (tt, J = 11.4, 3.3 Hz, 1H), 3.16 (tt, J =12.3, 3.3 Hz, 1H), 3.36 (d, J = 13.5 Hz, 1H), 3.46 (d, J = 12.9 Hz, 1H),6.77 (d, J = 3.3 Hz, 1H), 7.38 (d, J = 3.3 Hz, 1H), 7.50 (dd, J = 7.5,4.2 Hz, 1H), 8.10 (d, J = 8.1 Hz, 1H), 8.55 (dd, J = 5.1, 1.2 Hz, 1H),8.81 (d, J = 1.2 Hz, 1H), 9.27 (s, 1H). LC/MS: condition 1, retentiontime = 0.39 min LC/MS (ESI⁺) m/z; 446 [M + H]⁺ LC/MS (ESI⁻) m/z; 444 [M− H]⁻ 386b ¹H-NMR (CD₃OD) δ: 1.43 (m, 2H), 1.84 (m, 2H), 2.09 (m, 4H),2.49 (s, 3H), 2.69 (tt, J = 11.1, 3.6 Hz, 1H), 3.17 (tt, J = 12.3, 3.3Hz, 1H), 3.38 (d, J = 13.2 Hz, 1H), 3.45 (d, J = 12.9 Hz, 1H), 6.77 (d,J = 3.3 Hz, 1H), 7.31 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 3.3 Hz, 1H),7.57 (d, J = 8.7 Hz, 2H), 9.27 (s, 1H). LC/MS: condition 1, retentiontime = 2.92 min LC/MS (ESI⁺) m/z; 491 [M + H]⁺ LC/MS (ESI⁻) m/z; 489 [M− H]⁻ 387b ¹H-NMR (CD₃OD) δ: 1.40 (m, 2H), 1.85 (m, 2H), 2.10 (m, 4H),2.65 (tt, J = 11.4, 3.6 Hz, 1H), 3.17 (tt, J = 12.3, 3.6 Hz, 1H), 3.35(d, J = 13.5 Hz, 1H), 3.42 (d, J = 13.2 Hz, 1H), 3.93 (s, 3H), 6.77 (d,J = 3.3 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 3.3 Hz, 1H),7.89 (s, 1H), 8.38 (d, J = 2.4 Hz, 1H), 9.27 (s, 1H). LC/MS: condition1, retention time = 2.49 min LC/MS (ESI⁺) m/z; 476 [M + H]⁺ LC/MS (ESI⁻)m/z; 474 [M − H]⁻ 388b ¹H-NMR (CD₃OD) δ: 1.42 (m, 2H), 1.82 (m, 2H),2.10 (m, 4H), 2.68 (tt, J = 11.4, 3.6, 1H), 3.17 (tt, J = 12.6, 3.3 Hz,1H), 3.37 (d, J = 13.2 Hz, 1H), 3.43 (d, 13.2 Hz, 1H), 3.81 (s, 3H),6.77 (d, J = 3.3 Hz, 1H), 6.97 (d, J = 9.0 Hz, 2H), 7.38 (d, J = 3.3 Hz,1H), 7.56 (d, J = 8.4 Hz, 2H), 9.27 (s, 1H). LC/MS: condition 1,retention time = 2.75 min LC/MS (ESI⁺) m/z; 475 [M + H]⁺ LC/MS (ESI⁻)m/z; 473 [M − H]⁻

TABLE^(a) 143 Ex Data 389b ¹H-NMR (CDCl₃) δ: 0.87 (m, 2H), 1.34 (m, 2H),1.73 (m, 2H), 1.96 (m, 2H), 2.15 (m, 4H), 2.68-2.79 (m, 3H), 3.18 (m,1H), 6.77 (d, J = 3.3 Hz, 1H), 6.90-7.04 (m, 4H), 7.28 (d, J = 3.3 Hz,1H), 9.16 (br s, 1H), 9.21 (s, 1H). LC/MS: condition 1, retention time =2.75 min LC/MS (ESI⁺) m/z; 405 [M + H]⁺ LC/MS (ESI⁻) m/z; 403 [M − H]⁻390b ¹H-NMR (CDCl₃) δ: 1.33 (m, 2H), 1.92 (m, 2H), 2.17 (m, 4H), 2.68(tt, J = 11.1, 3.3, 1H), 3.08 (d, J = 12.6 Hz, 1H), 3.16 (tt, J = 12.3,3.9 Hz, 1H), 3.58 (d, J = 12 Hz, 1H), 3.89 (s, 3H), 3.60 (s, 3H), 6.73(d, J = 3.0 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H),7.21 (m, 1H), 7.29 (m, 1H), 9.21 (s, 1H), 9.41 (br s, 1H). LC/MS:condition 1, retention time = 2.67 min LC/MS (ESI⁺) m/z; 505 [M + H]⁺LC/MS (ESI⁻) m/z; 503 [M − H]⁻ 391b ¹H-NMR (CD₃OD) δ: 1.40 (m, 2H), 1.90(m, 2H), 2.14 (m, 4H), 2.71 (m, 1H), 2.94 (s, 4H), 3.29 (m, 1H), 6.82(d, J = 3.3 Hz, 1H), 7.40 (d, J = 3.3 Hz, 1H), 7.46 (d, J = 8.1 Hz, 2H),7.67 (d, J = 8.4 Hz, 2H) 9.30 (s, 1H). LC/MS: condition 1, retentiontime = 1.62 min LC/MS (ESI⁺) m/z; 386 [M + H]⁺ LC/MS (ESI⁻) m/z; 384 [M− H]⁻ 392b ¹H-NMR (CDCl₃) δ: 0.40 (m, 2H), 0.50 (m, 2H), 1.37 (m, 2H),1.98 (m, 2H), 2.14-2.26 (m, 5H), 2.82 (m, 1H), 3.18 (tt, J = 12.3, 3.3Hz, 1H), 3.71, 6.78 (d, J = 3.3 Hz, 1H), 7.30 (d, J = 3.3 Hz, 1H), 9.23(s, 1H). LC/MS: condition 1, retention time = 3.55 min LC/MS (ESI⁺) m/z;424 [M + H]⁺ LC/MS (ESI⁻) m/z; 422 [M − H]⁻ 393b ¹H-NMR (CDCl₃) δ: 1.42(m, 2H), 1.95-2.20 (m, 6H), 2.92 (m, 1H), 3.21 (tt, J = 12.6, 3.6 Hz,1H), 3.71 (d, J = 7.8 Hz, 2H), 6.78 (d, J = 3.3 Hz, 1H), 7.31 (d, J =3.3 Hz, 1H), 9.23 (s, 1H). LC/MS: condition 1, retention time = 0.35 minLC/MS (ESI⁺) m/z; 296 [M + H]⁺ LC/MS (ESI⁻) m/z; 294 [M − H]⁻ 394b¹H-NMR (CDCl₃) δ: 1.37 (m, 2H), 1.96 (m, 2H), 2.16 (m, 4H), 2.56 (t, J =6.6 Hz, 2H), 2.71 (tt, J = 11.7, 3.6 Hz, 1H), 3.04 (t, J = 6.6 Hz, 2H),3.18 (tt, J = 11.7, 3.9 Hz, 1H), 6.77 (dd, J = 3.3, 2.1 Hz, 1H), 7.30(t, J = 2.7 Hz, 1H), 9.22 (s, 1H), 9.36 (br s, 1H). LC/MS: condition 1,retention time = 0.35 min LC/MS (ESI⁺) m/z; 310 [M + H]⁺ LC/MS (ESI⁻)m/z; 308 [M − H]⁻

TABLE^(a) 144 Ex Data 395b ¹H-NMR (CDCl₃) δ: 1.38 (m, 2H), 1.96 (m, 2H),2.17 (m, 4H), 2.78 (tt, J = 11.1, 3.3 Hz, 1H), 3.18 (tt, J = 12.4, 3.3Hz, 1H), 3.29 (q, J = 9.6 Hz, 2H), 6.76 (dd, J = 3.3, 2.1 Hz, 1H), 7.30(t, J = 2.7 Hz, 1H), 9.22 (s, 1H), 9.43 (br s, 1H). LC/MS: condition 1,retention time = 0.37 min LC/MS (ESI⁺) m/z; 339 [M + H]⁺ LC/MS (ESI⁻)m/z; 337 [M − H]⁻ 396b ¹H-NMR (CDCl₃) δ: 0.16 (m, 2H), 0.51 (m, 2H),1.01 (m, 1H), 1.42 (m, 2H), 1.98 (m, 2H), 2.17 (m, 4H), 2.60 (d, J = 6.9Hz, 2H), 2.72 (tt, J = 11.1, 3.9 Hz, 1H), 3.19 (tt, J = 12.3, 3.3 Hz,1H), 6.77 (d, J = 3.3 Hz, 1H), 7.31 (d, J = 3.3 Hz, 1H), 9.23 (s, 1H).LC/MS: condition 1, retention time = 0.37 min LC/MS (ESI⁺) m/z; 311 [M +H]⁺ LC/MS (ESI⁻) m/z; 309 [M − H]⁻ 397b ¹H-NMR (CD₃OD) δ: 1.51 (m, 2H),1.95 (m, 2H), 2.18 (m, 4H), 2.39 (s, 6H), 2.42 (m, 1H), 3.15 (tt, J =11.7, 3.9 Hz, 1H), 6.79 (d, J = 3.3 Hz, 1H), 7.29 (d, J = 3.3 Hz, 1H),9.22 (s, 1H). LC/MS: condition 1, retention time = 0.35 min LC/MS (ESI⁺)m/z; 285 [M + H]⁺ LC/MS (ESI⁻) m/z; 283 [M − H]⁻ 398b ¹H-NMR (CDCl₃) δ:1.33 (m, 2H), 1.93 (m, 2H), 2.15 (m, 4H), 2.51 (s, 3H), 2.56 (m, 1H),3.18 (tt, J = 12.3, 3.6 Hz, 1H), 6.78 (d, J = 3.6 Hz, 1H), 7.28 (d, J =3.3 Hz, 1H), 9.21 (s, 1H). LC/MS: condition 1, retention time = 0.35 minLC/MS (ESI⁺) m/z; 271 [M + H]⁺ LC/MS (ESI⁻) m/z; 269 [M − H]⁻ 399b¹H-NMR (CDCl₃) δ: 1.37 (m, 2H), 1.97 (m, 2H), 2.17 (m, 4H), 2.72 (tt, J= 11.4, 3.6 Hz, 1H), 3.08 (td, J = 15.3, 4.5 Hz, 2H), 3.18 (tt, J =12.3, 3.3 Hz, 1H), 5.88 (m, 1H), 6.77 (m, 1H), 7.31 (m, 1H), 9.23 (s,1H), 9.59 (br s, 1H). LC/MS: condition 3, retention time = 0.81 minLC/MS (ESI⁺) m/z; 321 [M + H]⁺ LC/MS (ESI⁻) m/z; 319 [M − H]⁻ 400b¹H-NMR (CDCl₃) δ: 1.45 (m, 2H), 1.96 (m, 2H), 2.16 (m, 4H), 2.97 (m,1H), 3.18 (tt, J = 12.0, 3.6 Hz, 1H), 3.79 (m, 1H), 6.77 (m, 1H), 7.31(m, 1H), 9.17 (br s, 1H), 9.23 (s, 1H). LC/MS: condition 1, retentiontime = 4.04 min LC/MS (ESI⁺) m/z; 407 [M + H]⁺ LC/MS (ESI⁻) m/z; 405 [M− H]⁻ 401 ¹H-NMR (CD₃OD) δ: 1.71-2.18 (m, 9H), 3.33-3.45 (m, 1H), 3.67(d, J = 6.6 Hz, 2H), 6.80 (d, J = 3.3 Hz, 1H), 7.39 (d, J = 3.3 Hz, 1H),9.30 (s, 1H). LC/MS: condition 3, retention time = 1.53 min LC/MS (ESI⁺)m/z; 272 [M + H]⁺ LC/MS (ESI⁻) m/z; 270 [M − H]⁻

TABLE^(a) 145 Ex Data 402 ¹H-NMR (CDCl₃) δ: 1.76-1.91 (m, 2H), 1.95-2.06(m, 4H), 2.32-2.44 (m, 2H), 2.54-2.64 (m, 1H), 3.26-3.38 (m, 1H), 6.78(dd, J = 3.3, 1.8 Hz, 1H), 7.29 (t, J = 3.0 Hz, 1H), 9.19 (br s, 1H),9.22 (s, 1H), 9.84 (s, 1H). LC/MS: condition 3, retention time = 1.71min LC/MS (ESI⁺) m/z; 270 [M + H]⁺ LC/MS (ESI⁻) m/z; 268 [M − H]⁻ 403¹H-NMR (DMSO-d₆) δ: 1.56-1.99 (m, 10H), 2.39 (d, J = 6.3 Hz, 2H), 2.65(dd, J = 7.4, 6.0 Hz, 2H), 3.50 (dd, J = 7.4, 6.0 Hz, 2H), 4.14 (dd, J =9.8, 3.3 Hz, 2H), 6.76 (d, J = 3.3 Hz, 1H), 7.47 (d, J = 3.3 Hz, 1H),9.50 (s, 1H), 12.50 (br s, 1H). LC/MS: condition 1, retention time =0.94 min LC/MS (ESI⁺) m/z; 327 [M + H]⁺ 404 ¹H-NMR (DMSO-d₆) δ:1.47-1.62 (m, 1H), 1.63-1.85 (m, 4H), 1.89-2.07 (m, 3H), 2.24-2.59 (m,6H), 2.65-2.75 (m, 1H), 3.22-3.44 (m, 1H), 4.08-4.29 (m, 1H), 4.62 (d, J= 4.5 Hz, 1H), 2.86-2.98 (m, 1H), 3.29-3.39 (m, 1H), 6.77 (d, J = 3.3Hz, 1H), 7.48 (d, J = 3.3 Hz, 1H), 9.51 (s, 1H), 12.51 (br s, 1H).LC/MS: condition 3, retention time = 0.95 min LC/MS (ESI⁺) m/z; 341 [M +H]⁺ 405 ¹H-NMR (CDCl₃) δ: 1.59-1.96 (m, 7H), 2.06-2.31 (m, 5H),2.42-2.61 (m, 3H), 2.75 (d, J = 9.8 Hz, 1H), 2.86-2.98 (m, 1H),3.29-3.39 (m, 1H), 4.26-4.37 (m, 1H), 6.77 (d, J = 3.3 Hz, 1H), 7.28 (d,J = 3.3 Hz, 1H), 9.22 (s, 1H), 9.30 (br s, 1H). LC/MS: condition 3,retention time = 1.20 min LC/MS (ESI⁺) m/z; 341 [M + H]⁺ 406 ¹H-NMR(CDCl₃) δ: 0.31-0.49 (m, 4H), 1.54-1.98 (m, 7H), 2.09-2.42 (m, 3H), 2.78(d, J = 6.6 Hz, 2H), 3.36-3.44 (m, 1H), 6.78 (d, J = 3.0 Hz, 1H), 7.29(d, J = 3.0 Hz, 1H), 9.23 (s, 1H), 9.27 (br s, 1H). LC/MS: condition 3,retention time = 1.29 min LC/MS (ESI⁺) m/z; 311 [M + H]⁺ 407 ¹H-NMR(DMSO-d₆) δ: 1.21-1.38 (m, 2H), 1.70-1.83 (m, 4H), 1.91-2.07 (m, 3H),3.08-3.19 (m, 1H), 3.33 (dd, J = 18.4, 7.8 Hz, 2H), 4.11 (s, 1H),4.20-4.27 (m, 3H), 6.79-6.83 (m, 1H), 7.49 (q, J = 2.5 Hz, 1H), 9.51 (s,1H), 12.52 (br s, 1H). LC/MS: condition 1, retention time = 3.60 minLC/MS (ESI⁺) m/z; 420 [M + H]⁺ LC/MS (ESI⁻) m/z; 418 [M − H]⁻ 408 ¹H-NMR(DMSO-d₆) δ: 1.21-1.36 (m, 2H), 1.69-1.90 (m, 5H), 1.98-2.07 (m, 2H),3.08-3.19 (m, 1H), 3.26-3.34 (m, 2H), 4.18 (s, 2H), 4.43 (s, 2H),6.78-6.83 (m, 1H), 7.49-7.52 (m, 1H), 9.52 (s, 1H), 12.54 (br s, 1H).LC/MS: condition 1, retention time = 3.09 min LC/MS (ESI⁺) m/z; 377 [M +H]⁺ LC/MS (ESI⁻) m/z; 375 [M − H]⁻

TABLE^(a) 146 Ex Data 409 ¹H-NMR (DMSO-d₆) δ: 0.81-0.89 (m, 4H),1.17-1.30 (m, 2H), 1.70-1.89 (m, 5H), 1.98-2.07 (m, 2H), 2.74-2.81 (m,1H), 3.10-3.20 (m, 1H), 3.25 (d, J = 7.6 Hz, 2H), 4.16 (s, 2H),6.81-6.85 (m, 1H), 7.47-7.52 (m, 1H), 9.52 (s, 1H), 12.53 (br s, 1H).LC/MS: condition 1, retention time = 3.38 min LC/MS (ESI⁺) m/z; 378 [M +H]⁺ LC/MS (ESI⁻) m/z; 376 [M − H]⁻ 410 LC/MS: condition 1, retentiontime = 3.72 min LC/MS (ESI⁺) m/z; 432 [M + H]⁺ LC/MS (ESI⁻) m/z; 430 [M− H]⁻ 411 ¹H-NMR (DMSO-d₆) δ: 1.13-1.38 (m, 2H), 1.70-1.85 (m, 4H),1.89-2.06 (m, 4H), 3.08-3.21 (m, 1H), 3.21-3.32 (m, 1H), 3.38 (d, J =7.3 Hz, 2H), 3.76-3.89 (m, 1H), 4.21-4.32 (m, 1H), 6.80-6.84 (m, 1H),7.47-7.52 (m, 1H), 9.52 (s, 1H), 12.53 (br s, 1H). LC/MS: condition 1,retention time = 3.97 min LC/MS (ESI⁺) m/z; 463 [M + H]⁺ LC/MS (ESI⁻)m/z; 461 [M − H]⁻ 412 ¹H-NMR (DMSO-d₆) δ: 1.22-1.41 (m, 2H), 1.69-1.96(m, 5H), 1.98-2.08 (m, 2H), 3.10-3.22 (m, 1H), 3.37 (d, J = 7.3 Hz, 2H),3.71-3.86 (m, 2H), 4.44 (s, 2H), 6.79-6.82 (m, 1H), 7.48-7.53 (m, 1H),9.53 (s, 1H), 12.54 (br s, 1H). LC/MS: condition 1, retention time =3.54 min LC/MS (ESI⁺) m/z; 420 [M + H]⁺ LC/MS (ESI⁻) m/z; 418 [M − H]⁻413 ¹H-NMR (CDCl₃) δ: 0.15 (m, 2H), 0.55 (m, 2H), 0.90 (m, 1H), 1.48 (m,2H), 1.90-2.04 (m, 4H), 2.18 (m, 2H), 2.61 (d, J = 6.0 Hz, 2H), 2.97 (m,1H), 3.12 (m, 1H), 3.18 (q, J = 9.6 Hz, 2H), 6.79 (d, J = 3.3 Hz, 1H),7.30 (m, 1H), 9.22 (s, 1H), 9.29 (br s, 1H). LC/MS: condition 1,retention time = 3.85 min LC/MS (ESI⁺) m/z; 393 [M + H]⁺ LC/MS (ESI⁻)m/z; 391 [M − H]⁻ 414 ¹H-NMR (DMSO-d₆) δ: 0.12-0.19 (m, 2H), 0.48-0.55(m, 2H), 0.78-0.90 (m, 1H), 1.08-1.25 (m, 2H), 1.69-2.05 (m, 6H),2.33-2.39 (m, 5H), 3.09-3.21 (m, 1H), 3.87 (s, 2H), 6.83-6.86 (m, 1H),7.49 (t, J = 3.0 Hz, 1H), 9.51 (s, 1H), 12.52 (br s, 1H). LC/MS:condition 1, retention time = 3.74 min LC/MS (ESI⁺) m/z; 364 [M + H]⁺LC/MS (ESI⁻) m/z; 362 [M − H]⁻ 415 ¹H-NMR (DMSO-d₆) δ: 0.10-0.16 (m,2H), 0.44-0.52 (m, 2H), 0.83-0.94 (m, 1H), 1.05-1.21 (m, 2H), 1.54-1.68(m, 1H), 1.68-1.84 (m, 2H), 1.92-2.06 (m, 4H), 2.44-2.58 (m, 4H),3.09-3.21 (m, 1H), 3.25-3.39 (m, 2H), 6.80-6.84 (m, 1H), 7.47-7.51 (m,1H), 9.51 (s, 1H), 12.52 (br s, 1H). LC/MS: condition 1, retention time= 4.45 min LC/MS (ESI⁺) m/z; 407 [M + H]⁺ LC/MS (ESI⁻) m/z; 405 [M − H]⁻

TABLE^(a) 147 Ex Data 416 ¹H-NMR (DMSO-d₆) δ: 1.16-1.28 (m, 3H),1.67-1.88 (m, 3H), 1.93-2.01 (m, 2H), 2.11-2.19 (m, 2H), 2.40 (d, J =5.7 Hz, 2H), 3.10 (tt, J = 11.9, 3.7 Hz, 1H), 6.77-6.80 (m, 1H), 7.48(t, J = 2.9 Hz, 1H), 9.50 (s, 1H), 12.50 (br s, 1H). LC/MS: condition 1,retention time = 2.75 min LC/MS (ESI⁺) m/z; 336 [M + H]⁺ LC/MS (ESI⁻)m/z; 334 [M − H]⁻ 417 LC/MS: condition 1, retention time = 3.30 minLC/MS (ESI⁺) m/z; 375 [M + H]⁺ LC/MS (ESI⁻) m/z; 373 [M − H]⁻ 418 ¹H-NMR(DMSO-d₆) δ: 1.39 (qd, J = 12.6, 3.0 Hz, 2H), 1.72-1.87 (m, 2H),1.97-2.15 (m, 4H), 2.71-2.80 (m, 1H), 2.79 (s, 6H), 2.99 (d, J = 6.6 Hz,2H), 3.15 (tt, J = 12.2, 3.3 Hz, 1H), 6.81 (dd, J = 3.3, 2.0 Hz, 1H),7.50 (t, J = 3.0 Hz, 1H), 9.52 (s, 1H), 12.54 (br s, 1H). LC/MS:condition 1, retention time = 3.30 min LC/MS (ESI⁺) m/z; 363 [M + H]⁺LC/MS (ESI⁻) m/z; 361 [M − H]⁻ 419 LC/MS: condition 1, retention time =3.13 min LC/MS (ESI⁺) m/z; 374 [M + H]⁺ LC/MS (ESI⁻) m/z; 372 [M − H]⁻420 LC/MS: condition 3, retention time = 1.89 min LC/MS (ESI⁺) m/z; 417[M + H]⁺ LC/MS (ESI⁻) m/z; 415 [M − H]⁻ 421 ¹H-NMR (CDCl₃) δ: 1.07-1.30(m, 2H), 1.80-2.04 (m, 4H), 2.06-2.19 (m, 2H), 2.44 (d, J = 6.6 Hz, 2H),2.92-3.04 (m, 2H), 3.07-3.19 (m, 1H), 3.67-3.78 (m, 2H), 3.76 (d, J =8.3 Hz, 1H), 3.82 (d, J = 8.3 Hz, 1H), 4.20-4.32 (m, 1H), 6.75-6.80 (m,1H), 7.23-7.29 (m, 1H), 9.10 (br s, 1H), 9.20 (s, 1H). LC/MS: condition3, retention time = 1.52 min LC/MS (ESI⁺) m/z; 409 [M + H]⁺ 422 ¹H-NMR(CDCl₃) δ: 1.12-1.30 (m, 3H), 1.51 (s, 3H), 1.84-2.18 (m, 7H), 2.43 (d,J = 6.9 Hz, 2H), 3.06 (d, J = 8.3 Hz, 2H), 3.09-3.20 (m, 1H), 3.35 (d, J= 8.3 Hz, 2H), 6.75-6.81 (m, 1H), 7.22-7.29 (m, 1H), 9.13 (br s, 1H),9.21 (s, 1H). LC/MS: condition 3, retention time = 1.12 min LC/MS (ESI⁺)m/z; 341 [M + H]⁺ 423 ¹H-NMR (DMSO-d₆) δ: 1.08-1.24 (m, 2H), 1.35-1.50(m, 1H), 1.65-1.81 (m, 2H), 1.83-2.01 (m, 4H), 2.00 (s, 6H), 2.29 (d, J= 6.6 Hz, 2H), 2.68-2.75 (m, 3H), 3.11 (tt, J = 12.6, 3.6 Hz, 1H),3.37-3.42 (m, 2H), 6.79 (d, J = 3.3 Hz, 1H), 7.47 (d, J = 3.3 Hz, 1H),9.49 (s, 1H), 12.55 (br s, 1H). LC/MS: condition 1, retention time =0.34 min LC/MS (ESI⁺) m/z; 354 [M + H]⁺ LC/MS (ESI⁻) m/z; 352 [M − H]⁻

TABLE^(a) 148 Ex Data 424 ¹H-NMR (DMSO-d₆) δ: 0.94 (t, J = 7.3 Hz, 3H),1.15 (qd, J = 12.6, 2.6 Hz, 2H), 1.36-1.50 (m, 1H), 1.73 (qd, J = 12.6,2.6 Hz, 2H), 1.84-2.03 (m, 4H), 1.98 (s, 3H), 2.20 (q, J = 7.3 Hz, 2H),2.29 (d, J = 6.6 Hz, 2H), 2.69 (t, J = 6.9 Hz, 2H), 2.81-2.92 (m, 1H),3.11 (tt, J = 11.6, 3.3 Hz, 1H), 3.43 (t, J = 6.9 Hz, 2H), 6.80 (d, J =3.3 Hz, 1H), 7.48 (d, J = 3.3 Hz, 1H), 9.51 (s, 1H), 12.53 (br s, 1H).LC/MS: condition 1, retention time = 0.34 min LC/MS (ESI⁺) m/z; 368 [M +H]⁺ LC/MS (ESI⁻) m/z; 366 [M − H]⁻ 425 ¹H-NMR (DMSO-d₆) δ: 1.05-1.27 (m,2H), 1.27-1.45 (m, 1H), 1.54-1.82 (m, 2H), 1.83-2.04 (m, 4H), 2.38 (d, J= 6.6 Hz, 1H), 3.03-3.12 (m, 1H), 3.13 (d, J = 9.5 Hz, 2H), 3.55 (d, J =9.5 Hz, 2H), 6.80 (dd, J = 3.0, 2.1 Hz, 2H), 6.82 (s, 1H), 7.47 (t, J =3.0 Hz, 1H), 9.50 (s, 1H), 12.50 (s, 1H). LC/MS: condition 3, retentiontime = 1.32 min LC/MS (ESI⁺) m/z; 395 [M + H]⁺ LC/MS (ESI⁻) m/z; 393 [M− H]⁻ 426 LC/MS: condition 3, retention time = 1.42 min LC/MS (ESI⁺)m/z; 436 [M + H]⁺ LC/MS (ESI⁻) m/z; 434 [M − H]⁻ 427 ¹H-NMR (DMSO-d₆) δ:1.10-1.30 (m, 2H), 1.49-1.64 (m, 1H), 1.66-1.84 (m, 2H), 1.86-2.08 (m,4H), 2.82-2.93 (m, 5H), 3.06-3.22 (m, 1H), 6.80 (dd, J = 3.0, 2.1 Hz,1H), 7.01 (t, J = 6.3 Hz, 1H), 7.48 (t, J = 3.0 Hz, 1H), 9.51 (s, 1H),12.5 (s, 1H). LC/MS: condition 3, retention time = 1.57 min LC/MS (ESI⁺)m/z; 349 [M + H]⁺ LC/MS (ESI⁻) m/z; 347 [M − H]⁻ 428 ¹H-NMR (DMSO-d₆) δ:1.09-1.28 (m, 2H), 1.40 (s, 9H), 1.64-1.85 (m, 2H), 1.87-2.07 (m, 5H),2.39-2.57 (m, 2H), 3.05-3.26 (m, 1H), 3.57 (brs, 2H), 4.32 (d, J = 10.2Hz, 2H), 4.62 (d, J = 10.2 Hz, 2H), 6.93 (d, J = 3.3 Hz, 1H), 7.75 (d, J= 3.3 Hz, 1H), 9.62 (s, 1H). LC/MS: condition 3, retention time = 2.09min LC/MS (ESI⁺) m/z; 465 [M + H]⁺ 429 ¹H-NMR (DMSO-d₆) δ: 1.40-1.59 (m,2H), 1.71-2.10 (m, 6H), 2.26-2.40 (m, 1H), 3.09-3.26 (m, 1H), 6.80-6.87(m, 1H), 6.54 (d, J = 6.8 Hz, 0.2H), 7.31 (d, J = 4.8 Hz, 0.8H), 9.51(s, 1H), 10.4 (s, 0.8H), 10.7 (s, 0.2H), 12.51 (s, 1H). LC/MS: condition3, retention time = 1.51 min LC/MS (ESI⁺) m/z; 271 [M + H]⁺ 430 ¹H-NMR(CDCl₃) δ: 1.76-2.06 (m, 4H), 2.16-2.28 (m, 2H), 2.30-2.41 (m, 2H),2.58-2.73 (m, 1H), 3.17-3.30 (m, 1H), 6.75 (dd, J = 3.3, 1.8 Hz, 1H),7.31 (t, J = 3.3 Hz, 1H), 9.15 (br s, 1H), 9.22 (s, 1H). LC/MS:condition 3, retention time = 1.68 min LC/MS (ESI⁺) m/z; 267 [M + H]⁺LC/MS (ESI⁻) m/z; 265 [M − H]⁻

TABLE^(a) 149 Ex Data 431 ¹H-NMR (CDCl₃) δ: 1.48-1.65 (m, 2H), 1.95-2.13(m, 4H), 2.19-2.33 (m, 2H), 2.85-3.02 (m, 1H), 3.15-3.29 (m, 1H), 6.76(dd, J = 3.3, 2.1 Hz, 1H), 7.23 (d, J = 10.4 Hz, 1H), 7.31 (t, J = 3.3Hz, 1H), 9.20 (br s, 1H), 9.23 (s, 1H). LC/MS: condition 3, retentiontime = 1.99 min LC/MS (ESI⁺) m/z; 318 [M + H]⁺ LC/MS (ESI⁻) m/z; 316 [M− H]⁻ 432 ¹H-NMR (DMSO-d₆) δ: 1.21-1.39 (m, 2H), 1.54-1.67 (m, 1H),1.68-1.86 (m, 2H), 1.87-2.11 (m, 6H), 3.08-3.22 (m, 1H), 4.92 (t, J =7.4 Hz, 1H), 6.80 (dd, J = 3.0, 1.8 Hz, 1H), 7.49 (t, J = 3.0 Hz, 1H),9.51 (s, 1H), 12.51 (s, 1H). LC/MS: condition 3, retention time = 1.93min LC/MS (ESI⁺) m/z; 320 [M + H]⁺ LC/MS (ESI⁻) m/z; 318 [M − H]⁻ 433¹H-NMR (DMSO-d₆) δ: 1.70-1.90 (m, 2H), 2.00-2.18 (m, 2H), 2.23-2.80 (m,4H), 3.20-3.50 (m, 1H), 4.72 (s, 2H), 6.81 (d, J = 2.7 Hz, 1H), 7.49 (d,J = 1.8 Hz, 1H), 9.51 (s, 1H), 12.52 (br s, 1H). LC/MS: condition 1,retention time = 3.79 min LC/MS (ESI⁺) m/z; 254 [M + H]⁺ LC/MS (ESI⁻)m/z; 252 [M − H]⁻ 434 ¹H-NMR (CDCl₃) δ: 2.13 (m, 2H), 2.30 (m, 2H), 2.45(m, 2H), 2.68 (m, 1H), 3.13 (m, 1H), 3.50 (tt, J = 11.4, 3.9 Hz, 1H),5.21 (s, 1H), 6.77 (t, J = 3.0 Hz, 1H), 7.34 (t, J = 3.0 Hz, 1H), 9.25(s, 1H), 9.38 (br s, 1H). LC/MS: condition 1, retention time = 3.37 minLC/MS (ESI⁺) m/z; 279 [M + H]⁺ LC/MS (ESI⁻) m/z; 277 [M − H]⁻ 435a¹H-NMR (CDCl₃) δ: 1.86 (m, 4H), 1.96 (m, 2H), 2.09 (m, 1H), 2.19 (m,2H), 2.42 (d, J = 7.5 Hz, 2H), 3.46 (m, 1H), 6.75 (t, J = 3.0 Hz, 1H),7.30 (t, J = 3.0 Hz, 1H), 9.23 (s, 1H), 9.25 (br s, 1H). LC/MS:condition 1, retention time = 3.38 min LC/MS (ESI⁺) m/z; 281 [M + H]⁺LC/MS (ESI⁻) m/z; 279 [M − H]⁻ 435b ¹H-NMR (CDCl₃) δ: 1.43 (m, 2H),1.84-2.01 (m, 3H), 2.05-2.26 (m, 2H), 2.20 (m, 2H), 2.41 (m, 2H), 3.18(tt, J = 12, 3.6 Hz, 1H), 6.78 (m, 1H), 7.31 (m, 1H), 9.23 (s, 1H), 9.47(br s, 1H). LC/MS: condition 1, retention time = 3.27 min LC/MS (ESI⁺)m/z; 281 [M + H]⁺ LC/MS (ESI⁻) m/z; 279 [M − H]⁻ 436 ¹H-NMR (CDCl₃) δ:1.31 (t, 3H), 2.03-2.32 (m, 5H), 2.40-2.58 (m, 2H), 3.50 (tt, J = 11.1,3.6 Hz, 1H), 3.96 (m, 1H), 4.20 (q, J = 6.9 Hz, 2H), 5.76 (s, 1H), 6.78(dd, J = 3.3, 2.1 Hz, 1H), 7.33 (t, J = 3.3 Hz, 1H), 9.26 (s, 1H), 10.02(br s, 1H). LC/MS: condition 1, retention time = 3.80 min LC/MS (ESI⁺)m/z; 326 [M + H]⁺ LC/MS (ESI⁻) m/z; 324 [M − H]⁻

TABLE^(A) 150 Ex Data 437 ¹H-NMR (CDCl₃) δ: 1.97 (s, 3H), 2.00-2.28 (m,5H), 2.44 (m, 1H), 2.90 (m, 1H), 3.13 (m, 1H), 3.48 (tt, J = 10.8, 3.9Hz, 1H), 6.76 (m, 1H), 7.31 (m, 1H), 9.17 (br s, 1H), 9.23 (s, 1H).LC/MS: condition 1, retention time = 3.54 min LC/MS (ESI⁺) m/z; 293 [M +H]⁺ LC/MS (ESI⁻) m/z; 291 [M − H]⁻ 438 ¹H-NMR (CDCl₃) δ: 1.28 (m, 6H),1.75 (m, 4H), 1.81-2.02 (m, 8H), 2.13-2.32 (m, 8H), 2.43 (d, J = 7.2 Hz,2H), 3.17 (tt, J = 11.7, 3.6 Hz, 1H), 3.39 (m, 1H), 4.16 (m, 4H), 6.78(m, 2H), 7.32 (m, 2H), 9.25 (s, 1H), 9.26 (s, 1H), 10.00 (br s, 2H).LC/MS: condition 1, retention time = 3.80 min (cis/trans mixture) LC/MS(ESI⁺) m/z; 328 [M + H]⁺ LC/MS (ESI⁻) m/z; 326 [M − H]⁻ 439a ¹H-NMR(CDCl₃) δ: 1.34 (d, J = 7.2 Hz, 3H), 1.42-1.61 (m, 5H), 1.80 (m, 2H),1.93 (m, 2H), 2.68 (quin, J = 7.2 Hz, 1H), 3.51 (m, 1H), 6.76 (m, 1H),7.29 (m, 1H), 9.23 (s, 1H). LC/MS: condition 1, retention time = 3.65min LC/MS (ESI⁺) m/z; 295 [M + H]⁺ LC/MS (ESI⁻) m/z; 293 [M − H]⁻ 439b¹H-NMR (CDCl₃) δ: 1.40 (m, 3H), 1.42-1.61 (m, 5H), 1.97 (m, 2H), 2.20(m, 2H), 2.65 (quin, J = 6.6 Hz, 1H), 3.19 (m, 1H), 6.79 (m, 1H), 7.31(m, 1H), 9.15 (br s, 1H), 9.23 (s, 1H). LC/MS: condition 1, retentiontime = 3.49 min LC/MS (ESI⁺) m/z; 295 [M + H]⁺ LC/MS (ESI⁻) m/z; 293 [M− H]⁻ 440 ¹H-NMR (CDCl₃) δ: 1.42 (m, 2H), 1.91-2.04 (m, 4H), 2.20 (m,2H), 2.36 (m, 1H), 3.16 (tt, J = 12.0, 3.6 Hz, 1H), 5.37 (dd, J = 16.5,1.5 Hz, 1H), 6.76 (dd, J = 16.5, 6.9 Hz, 1H), 6.77 (d, J = 3.3, 1H),7.29 (d, J = 3.3 Hz, 1H), 9.16 (br s, 1H), 9.22 (s, 1H). LC/MS:condition 1, retention time = 3.54 min LC/MS (ESI⁺) m/z; 293 [M + H]⁺LC/MS (ESI⁻) m/z; 291 [M − H]⁻ 441 ¹H-NMR (CDCl₃) δ: 1.24 (m, 2H),1.59-1.73 (m, 5H), 1.87-2.04 (m, 2H), 2.16 (m, 2H), 2.44 (t, J = 7.2 Hz,2H), 3.17 (tt, J = 12.3, 3.3 Hz, 1H), 6.78 (dd, J = 3.3, 2.1, 1H), 7.30(t, J = 3.3 Hz, 1H), 9.22 (s, 1H), 9.28 (br s, 1H). LC/MS: condition 1,retention time = 3.47 min LC/MS (ESI⁺) m/z; 295 [M + H]⁺ LC/MS (ESI⁻)m/z; 293 [M − H]⁻ 442a ¹H-NMR (CDCl₃) δ: 1.74 (m, 4H), 1.91-2.17 (m,6H), 2.31 (m, 1H), 3.40 (m, 1H), 3.93 (m, 2H), 6.77 (m, 1H), 7.25 (m,1H), 9.12 (br s, 1H), 9.22 (s, 1H). LC/MS: condition 1, retention time =3.42 min LC/MS (ESI⁺) m/z; 381 [M + H]⁺ LC/MS (ESI⁻) m/z; 379 [M − H]⁻

TABLE^(a) 151 Ex Data 442b ¹H-NMR (CDCl₃) δ: 1.74 (m, 2H), 1.98 (m, 4H),2.13 (m, 3H), 2.25 (m, 2H), 3.17 (m, 1H), 3.96 (m, 2H), 6.78 (m, 1H),7.28 (m, 1H), 9.07 (br s, 1H), 9.21 (s, 1H). LC/MS: condition 1,retention time = 3.30 min LC/MS (ESI⁺) m/z; 381 [M + H]⁺ LC/MS (ESI⁻)m/z; 379 [M − H]⁻ 443a ¹H-NMR (CD₃OD) 5: 1.75 (m, 4H), 1.94 (m, 3H),2.10-2.30 (m, 4H), 3.39 (m, 1H), 4.15 (s, 2H), 6.80 (d, J = 3.3 Hz, 1H),7.38 (d, J = 3.3 Hz, 1H), 9.29 (s, 1H). LC/MS: condition 1, retentiontime = 3.04 min LC/MS (ESI⁺) m/z; 338 [M + H]⁺ LC/MS (ESI⁻) m/z; 336 [M− H]⁻ 443b ¹H-NMR (CD₃OD) δ: 1.75-2.33 (m, 11H), 3.54 (m, 1H), 4.16 (s,2H), 6.83 (d, J = 3.3 Hz, 1H), 7.40 (d, J = 3.3 Hz, 1H), 9.29 (s, 1H).LC/MS: condition 1, retention time = 2.85 min LC/MS (ESI⁺) m/z; 338 [M +H]⁺ LC/MS (ESI⁻) m/z; 336 [M − H]⁻ 444 ¹H-NMR (CDCl₃) δ: 1.13 (m, 3H),1.33 (m, 2H), 2.13 (m, 6H), 3.19 (m, 1H), 6.83 (d, J = 3.3 Hz, 1H), 7.33(d, J = 3.3 Hz, 1H), 9.24 (s, 1H), 9.35 (br s, 1H). LC/MS: condition 1,retention time = 3.32 min LC/MS (ESI⁺) m/z; 293 [M + H]⁺ LC/MS (ESI⁻)m/z; 291 [M − H]⁻ 445 ¹H-NMR (DMSO-d₆) δ: 1.60-1.80 (m, 6H), 1.99-2.11(m, 6H), 2.26-2.32 (m, 2H), 4.60 (s, 1H), 6.83 (dd, J = 3.0, 1.7 Hz,1H), 7.52 (t, J = 3.0 Hz, 1H), 9.54 (s, 1H), 12.58 (br s, 1H). LC/MS:condition 1, retention time = 3.10 min LC/MS (ESI⁺) m/z; 310 [M + H]⁺LC/MS (ESI⁻) m/z; 308 [M − H]⁻

Pharmacological Assay

Now, a pharmacological assay of the tricyclic pyrimidine compounds ofthe present invention will be described.

Assay Example^(a) 1 Enzyme Assay

JAK1, JAK2, JAK3 and Tyk2 were purchased from Carna Biosciences, Inc. Asthe substrate, LANCE Ultra ULight-JAK1 Peptide (manufactured byPerkinElmer Co., Ltd. (PE)) was used. Dilute solutions of compounds andenzymes in assay buffer (50 mM HEPES pH7.5, 1 mM EGTA, 1 mM MgCl₂, 2 mMDTT, 0.01% Tween20) were dispensed into wells of a 384-well black plate.After 5 minutes of preincubation, dilute solutions of the substrate andATP (adenosine triphosphate) were added at a final concentration of 100μM, and the plate was incubated at room temperature for 2 hours. Afteraddition of a termination reagent containing EDTA (ehylenediaminetetraacetic acid) at a final concentration of 10 mM, LANCE Eu-W1024Anti-phosphotyrosine (PT66) (manufactured by PE) was added, and after 1hour of incubation, the fluorescences were measured with ARVO-HTS. Fromthe plot of logarithm of a compound concentration and inhibitoryactivity, the IC₅₀ was calculated. The results of JAK3, JAK1, JAK2 andTyk2 enzyme assays of the compounds of Synthetic Examples^(a) are shownin Tables^(a) 152 to 155. “*” in the Tables indicates IC₅₀>1 μM.

TABLE^(a) 152 Ex^(a). IC₅₀ (μM) IC₅₀ (μM) No. JAK3 JAK1 1 1.4 0.23 20.061 0.014 3 1.4 0.057 4 0.29 0.013 5 0.26 0.020 6 0.15 0.0038 7 0.0550.0042 8 0.43 0.020 9 0.43 0.030 10 0.19 0.0031

TABLE^(a) 153 EX^(a). IC₅₀ (μM) IC₅₀ (μM) No. JAK2 TYK2 1 0.31 0.59 20.017 0.059 3 0.13 * 4 0.026 0.23 5 0.13 0.13 6 0.012 0.046 7 0.0120.056 8 0.030 0.036 9 0.046 0.078 10 0.019 0.037

TABLE^(a) 154 Ex^(a). IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) No. JAK1JAK2 JAK3 TYK2  11 0.20 0.34 0.44 4.1  12 0.021 0.22 0.40 0.91  13 0.120.25 * *  14 0.021 0.11 1.0 2.2  15 0.29 2.5 4.3 *  16 0.28 0.57 5.3 2.6 17 0.029 0.076 2.1 0.57  18 0.21 0.62 * *  19 0.072 0.27 1.0 1.0  200.019 0.032 0.33 0.42  21 0.015 0.11 0.90 0.71  22 0.061 0.56 * 0.88  230.55 * * *  24 0.16 0.51 6.9 5.3  25 0.016 0.047 0.44 0.16  26 0.0280.21 * *  27 0.18 * * *  28 0.019 0.040 0.22 1.5  29 0.094 0.34 * *  300.0095 0.064 0.48 0.20  31 0.023 0.21 * *  32 0.0098 0.036 0.38 0.99  330.0025 0.019 0.078 0.63  34 0.0033 0.010 0.031 0.17  35 0.0049 0.0170.26 0.46  36 0.073 0.18 * *  37 0.0054 0.041 0.31 *  38 0.0046 0.0320.22 *  39 0.0049 0.028 0.53 *  40 0.0022 0.0064 0.037 0.15  41 0.00110.0061 0.042 0.15  42 0.082 0.41 * *  43 0.0027 0.014 0.054 0.10  440.0049 0.013 0.042 0.12  45 0.066 1.0 * *  46 0.025 0.17 * *  470.78 * * *  48 0.022 0.054 0.44 0.46  49 0.00061 0.0027 0.041 0.057  500.011 * * *  51 0.25 * * *  52 0.0021 0.018 0.041 0.36  53 0.000320.0015 0.024 0.047  54 0.0012 0.015 0.071 0.21  55 0.0061 0.030 0.220.39  56a 0.50 * * *  56b 0.035 0.60 * *  57 0.069 * * *  58 0.180.82 * *  59 0.032 0.18 * *  60 0.0051 0.032 * 4.2  61 0.016 0.15 0.530.44  62 0.0099 0.031 0.47 0.14  63 0.011 0.040 0.78 0.20  64 0.033 0.120.93 0.31  65 0.0031 0.013 0.15 0.025  66 0.0033 0.013 0.086 0.027  670.052 0.20 0.65 0.41  69 0.0047 0.026 * 0.041  71 0.00094 0.0028 0.0550.028  72 0.0021 0.0077 0.048 0.032  73 0.0019 0.014 0.065 0.011  740.00040 0.003 0.074 0.0026  75 0.00020 0.0010 0.032 0.0012  76 0.000330.0022 0.030 0.0097  77 0.0013 0.0054 0.053 0.044  78 0.0033 0.015 0.170.055  79 0.0030 0.020 0.39 0.043  81 0.012 0.053 0.64 0.15  82 0.0410.30 * 0.55  83 0.0091 0.048 0.28 0.096  84 0.018 0.089 0.62 0.54  850.053 0.31 * 0.50  86 0.020 0.17 0.48 *  88 0.0055 0.026 0.21 0.15  890.025 0.20 * 0.61  90 0.0047 0.026 0.20 0.044  91 0.018 0.094 0.64 0.32 92 0.0058 * * *  93 0.0075 0.061 0.31 0.0059  94 0.0041 0.041 0.83 0.25 95 0.0099 0.083 * 0.43  96 0.027 0.21 * *  97 0.021 0.10 0.97 *  980.0033 0.070 0.30 0.0026  99 0.060 0.42 * * 100 0.0093 0.045 0.24 0.47101 0.0026 0.046 0.22 0.0023 102 0.019 0.15 * * 103 0.016 0.17 * 0.47104 0.089 * * * 105 0.021 0.19 * 0.37 106 0.0019 0.041 0.28 0.0036 1070.0028 0.055 0.28 0.036 108 0.0039 0.024 0.58 0.58 109 0.0016 0.011 0.160.072 110 0.0056 0.091 0.51 0.0049 111 0.0019 0.027 0.22 0.028 1120.0049 0.079 0.25 0.0033 113 0.0078 0.089 0.71 0.0087 114 0.095 0.43 *0.87 115 0.13 0.40 * * 116 0.0033 0.032 0.56 0.19 117 0.039 0.36 * * 1180.015 0.035 * 0.13 119 0.0040 0.039 0.59 0.10 120 0.014 0.20 * 0.12 1210.0039 0.042 0.46 0.14 122 0.023 0.47 * 0.34 123 0.0061 0.19 0.87 0.23124 0.029 0.23 * 0.55 125 0.071 * * * 126 0.073 * * * 127 0.017 0.19 *0.42 128 0.14 * * * 129 0.0071 0.078 * 0.18 130 0.011 0.024 * 0.18 1310.0054 0.032 0.56 0.13 132 0.0050 0.034 * 0.11 133 0.12 * * * 134a 0.0220.095 1.0 0.37 134b 0.0022 0.024 0.66 0.056 135a 0.097 0.94 * * 135b0.0063 0.094 * 0.18 136a 0.14 * * * 136b 0.016 0.29 * 0.45 137a 0.0320.49 * 0.31 137b 0.0041 0.039 0.38 0.088 138a 0.023 0.74 * 0.25 138b0.0043 0.043 0.40 0.046 139a 0.26 0.40 0.43 * 139b 0.021 0.076 * 0.50140 0.028 0.039 0.50 0.13 141 0.0028 0.014 0.24 0.038 142 0.0080 0.0140.36 0.28 143 0.0025 0.0056 0.18 0.12 144 0.00066 0.0040 0.054 0.062 1450.0037 0.015 0.026 0.20 146 0.0091 0.020 0.31 0.17 147 0.0024 0.00490.18 0.16 148 0.0043 0.010 0.20 0.21 149 0.0014 0.0028 0.060 0.098 1500.00098 0.022 0.0098 0.091 151 0.049 0.072 0.63 * 152 0.0018 0.00370.032 0.11 153 0.0010 0.0023 0.015 0.11 154 0.0086 0.024 0.62 0.70 1550.011 0.032 0.95 * 156 0.0032 0.042 0.52 0.65 157 0.0020 0.020 0.24 0.31158 0.00070 0.0044 0.059 0.097 159 0.0016 0.011 0.080 0.30 160 0.00530.021 0.35 0.26 161 0.0034 0.011 0.31 0.14 162 0.032 0.20 0.68 * 1630.010 0.034 0.41 0.31 164 0.0058 0.030 0.23 0.29 165 0.0044 0.020 0.100.34 166 0.0053 0.023 0.17 0.49 167 0.0031 0.030 0.17 0.98 168 0.0840.71 * * 169 0.0050 0.052 0.58 * 170 0.021 0.11 0.52 * 171 0.10 0.94 * *172 0.013 0.093 * 0.63 173 0.034 0.26 * 0.46 174 0.0057 0.072 0.61 0.099175 0.0056 0.0074 0.34 0.045 176 0.034 0.19 * * 177 0.0029 0.031 0.200.0028 178 0.0026 0.024 0.17 0.053 179 0.028 0.094 * * 180 0.0013 0.00190.030 0.022 181 0.024 0.13 * 0.49 182 0.0054 0.039 0.28 0.016 183 0.00610.055 0.80 0.041 184 0.0035 0.042 0.58 0.087 185 0.0081 0.051 0.32 0.13186 0.0027 0.027 0.099 0.044 187 0.0076 0.038 0.37 0.36 188 0.00120.0084 0.11 0.063 189 0.011 0.038 0.61 0.38 190 0.022 0.098 * 0.61 1910.010 0.084 0.92 0.18 192 0.0039 0.038 0.32 0.10 193 0.0053 0.041 0.280.0055 194a 0.032 0.74 * 0.33 194b 0.0084 0.046 0.50 0.11 195a 0.0300.55 * 0.31 195b 0.0070 0.042 0.56 0.12 196a 0.060 0.75 * * 196b 0.00320.036 0.29 0.27 197a 0.016 0.40 * 0.15 197b 0.0054 0.045 0.52 0.11 198b0.0025 0.037 0.40 0.065 199b 0.0035 0.035 0.18 0.44 200b 0.0025 0.0320.076 0.24 201b 0.0039 0.066 0.41 0.10 202b 0.0034 0.085 0.68 0.26 203b0.0041 0.16 1.0 0.33 204b 0.0072 0.19 * 0.35 205 0.026 0.25 * 0.75 2060.27 * * * 207 0.0090 0.055 * * 208 0.0028 0.033 0.36 0.37 209 0.0610.42 * * 210 0.0047 0.019 0.077 0.29 211 0.12 0.74 * * 212 0.0054 0.0470.62 0.45

TABLE^(a) 155 Ex^(a). IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) No. JAK1JAK2 JAK3 TYK2 213 0.024 0.19 * * 214 0.0026 0.013 0.040 0.29 215 0.0260.25 * * 216 0.38 * * * 217 0.080 0.18 0.38 * 218 0.028 0.14 * * 2190.039 0.081 0.62 0.97 220 0.013 0.086 0.62 * 221 0.018 0.090 * * 2220.0035 0.033 0.32 0.77 223 0.015 0.031 0.94 * 224 0.0020 0.012 0.43 0.95225 0.021 0.20 * * 226 0.28 * * * 227 0.0025 0.021 0.079 0.57 228 0.00160.0044 0.17 0.10 229 0.039 0.087 * * 230 0.035 0.13 * * 231 0.0043 0.0230.23 0.61 232 0.0053 0.033 * 0.74 233 0.021 0.071 * * 234 0.36 0.88 * *235 0.056 0.37 * * 236 0.0068 0.052 0.45 * 237 0.0015 0.010 0.41 * 2380.00079 0.0046 0.055 0.11 239 0.0081 0.035 0.61 0.65 240 0.039 0.110.60 * 241 0.046 0.17 * * 242 0.0065 0.052 0.96 * 243 0.044 0.29 * * 2440.0054 0.038 0.44 0.79 245 0.017 0.062 * * 246 0.0053 0.019 0.28 0.14247 0.013 0.090 0.92 * 248 0.041 0.14 * * 249 0.017 0.056 0.49 0.86 2500.031 0.18 * * 251 0.031 0.20 * * 252 0.017 0.060 * * 253 0.0011 0.00660.14 0.044 254 0.0071 0.024 0.53 0.16 255 0.0025 0.015 0.24 0.14 2560.015 0.062 0.99 0.27 257 0.0017 0.016 0.49 0.049 258 0.012 0.081 * 0.74259 0.0021 0.0081 0.27 0.037 260 0.024 0.048 * 0.97 261 0.023 0.091 *0.64 262 0.0047 0.045 0.59 0.91 263 0.027 0.22 * * 264 0.011 0.032 * *265 0.046 0.18 * * 266 0.025 0.11 * 0.35 267 0.0010 0.032 0.79 0.019 2680.0044 0.036 0.72 0.12 269 0.0013 0.012 0.057 0.10 270 0.012 0.10 0.750.0048 271 0.020 0.063 * 0.43 272 0.0035 0.053 0.43 0.094 273 0.00460.021 0.57 0.24 274 0.0035 0.029 * 0.20 275 0.0067 0.065 0.85 0.52 2760.0029 0.049 0.063 0.032 277 0.0015 0.033 0.27 0.050 278 0.0043 0.0340.45 0.40 279 0.0074 0.044 0.53 0.20 280 0.0019 0.062 0.68 0.10 2810.0077 0.050 0.15 0.48 282 0.0052 0.070 0.39 0.080 283 0.014 0.11 0.900.23 284 0.017 0.15 * 0.32 285 0.0091 0.12 0.61 0.068 286 0.0059 0.0350.57 0.23 287 0.0065 0.077 * 0.33 288 0.046 0.15 0.15 0.37 289 0.0210.15 0.85 0.16 290 0.0076 0.039 0.50 0.27 291 0.0053 0.10 0.67 0.14 2920.0027 0.017 0.39 0.27 293 0.024 0.10 0.94 0.31 294 0.022 0.12 0.48 0.34295 0.0069 0.064 0.84 0.33 296 0.0038 0.065 0.73 0.19 297 0.0095 0.10 *0.32 298 0.019 0.11 * 0.59 299 0.016 0.17 * * 300 0.025 0.059 0.75 * 3010.024 0.072 0.96 * 302 0.012 0.029 0.49 0.36 303 0.057 0.35 * * 3040.049 0.27 * * 305 0.046 0.29 * * 306 0.015 0.054 * 0.62 307 0.00660.26 * * 308 0.0024 0.012 0.24 0.79 309 0.0076 0.097 * 0.31 310 0.0710.38 * * 311 0.025 0.16 * 0.94 312 0.012 0.045 * 0.37 313 0.0084 0.051 *0.51 314 0.0080 0.19 * 0.75 315 0.010 0.20 * 0.53 316 0.013 0.099 * 0.59317 0.0013 0.016 0.47 0.62 318 0.0048 0.057 * 0.61 319 0.027 0.23 * *320 0.0076 0.057 * 0.86 321 0.024 0.21 * * 322 0.0013 0.0071 0.20 0.43323 0.0051 0.034 0.83 0.78 324 0.0034 0.034 0.66 0.75 325 0.011 0.058 *0.88 326 0.048 0.31 * * 327 0.0070 0.054 0.79 0.55 328 0.0073 0.033 0.530.90 329 0.0048 0.029 0.80 0.21 330 0.0074 0.047 * 0.14 331 0.00880.054 * 0.42 332 0.012 0.045 * 0.49 333 0.0085 0.044 * 0.27 3340.064 * * * 335 0.029 0.29 * 0.71 336 0.025 0.37 * * 337 0.029 0.34 *0.51 338 0.0069 0.060 0.48 0.59 339 0.018 0.052 0.26 0.86 340 0.0210.23 * * 341 0.010 0.059 0.31 0.32 342 0.0039 0.034 0.13 0.35 343 0.0100.063 0.33 0.44 344 0.012 0.068 0.52 0.39 345 0.025 0.20 * * 346 0.00510.060 * * 347 0.0069 0.11 0.65 * 348 0.0099 0.051 0.75 0.29 349 0.00590.048 * 0.25 350 0.0080 0.047 * 0.54 351 0.012 0.089 * * 352 0.00500.029 * * 353 0.0029 0.031 0.35 0.46 354 0.0018 0.026 0.69 0.16 3550.0042 0.033 * 0.15 356 0.0036 0.036 * 0.16 357 0.067 0.33 * 0.87 3580.63 0.91 * * 359 0.042 0.22 * 0.56 360 0.026 0.10 * 0.33 361 0.0890.25 * * 362 0.0074 0.057 * * 363 0.044 0.29 * * 364 0.0057 0.011 0.390.21 365 0.0054 0.016 0.74 0.34 366 0.011 0.028 0.28 0.26 367 0.000990.0043 0.054 0.0073 368 0.0013 0.0061 0.37 0.030 369 0.00033 0.00170.048 0.0092 370 0.0074 0.097 0.59 * 371 0.0033 0.035 0.39 0.18 3720.0041 0.016 0.23 0.41 373 0.0015 0.011 0.035 0.53 374 0.038 0.18 * *375 0.047 0.33 * * 376 0.019 0.19 * * 377 0.0045 0.017 0.054 * 3780.0040 0.071 0.41 0.20 379 0.013 0.11 0.66 0.29 380 0.0020 0.0025 0.200.028 381a 0.069 0.22 0.26 * 381b 0.0066 0.057 0.42 0.24 382a 0.0150.063 0.75 0.76 382b 0.00031 0.0028 0.070 0.013 383a 0.090 0.37 * * 383b0.0015 0.013 0.50 0.17 384a 0.087 0.56 * * 384b 0.022 0.080 * * 385b0.0019 0.031 0.18 0.21 386b 0.0017 0.027 0.28 0.39 387b 0.0019 0.0320.12 0.18 388b 0.0012 0.025 0.26 0.21 389b 0.0079 0.14 * 0.67 390b0.0024 0.089 0.52 0.36 391b 0.018 0.39 * 0.58 392b 0.014 0.080 0.61 0.33393b 0.0062 0.030 0.79 0.38 394b 0.015 0.090 * * 395b 0.0022 0.010 0.610.15 396b 0.022 0.19 * 0.71 397b 0.023 0.21 * 0.80 398b 0.029 0.11 *0.75 399b 0.0075 0.029 * 0.20 400b 0.042 0.19 * 0.84 401 0.012 0.0360.36 0.15 402 0.011 0.030 0.13 0.10 403 0.040 0.30 0.44 0.81 404 0.110.35 0.32 * 405 0.025 0.25 * 0.77 406 0.083 0.56 * 0.94 407 0.00340.0073 0.31 0.13 408 0.0052 0.013 0.22 0.31 409 0.019 0.032 0.92 0.84410 0.022 0.040 0.32 0.58 411 0.0043 0.015 0.17 0.36 412 0.0026 0.00560.054 0.32 413 0.020 0.031 * 0.62 414 0.0095 0.13 * 0.11 415 0.0300.095 * * 416 0.029 0.047 * 0.68 417 0.0078 0.026 0.38 0.42 418 0.00430.0084 0.33 0.17 419 0.0035 0.0061 0.069 0.27 420 0.0057 0.015 0.41 0.30421 0.010 0.17 * * 422 0.0028 0.051 * 0.13 423 0.077 0.72 * * 424 0.0440.48 * * 425 0.0025 0.022 0.082 0.37 426 0.011 0.062 0.87 0.58 4270.00016 0.0012 0.030 0.016 428 0.19 0.75 * * 429 0.017 0.035 0.79 0.52430 0.0086 0.049 * 0.41 431 0.0048 0.013 0.29 0.24 432 0.0026 0.00880.17 0.067 433 0.0081 0.027 0.71 0.12 434 0.0023 0.014 0.49 0.034 435a0.0054 0.021 0.72 0.17 435b 0.00011 0.0025 0.032 0.0029 436 0.0350.17 * * 437 0.020 0.055 0.57 0.45 438 0.017 0.044 0.34 0.58 439a 0.130.34 * * 439b 0.0031 0.0067 0.33 0.025 440 0.0053 0.031 0.54 0.14 4410.0016 0.0046 0.12 0.024 442a 0.027 0.061 0.52 0.79 442b 0.0032 0.0140.10 0.88 443a 0.026 0.060 0.73 0.54 443b 0.010 0.030 0.34 * 444 0.00340.0090 0.25 0.045 445 0.031 0.13 0.22 0.052

The tricyclic pyrimidine compounds of the present invention havefavorable inhibitory activity against JAKs as shown above.

Assay Example^(a) 2 Signal Assay in Human Whole Blood

To be a effective pharmaceutical compound for the target diseases of thepresent invention, especially for rheumatoid arthritis, it is morefavorable that the compounds indicate excellent inhibitory activityagainst JAKs in human whole blood. Inhibitory activity against JAKs inhuman whole blood can be assessed by, for example, STAT phosphorylationassay in human whole blood as described below.

Compounds are added at the various concentrations to human whole bloodwhich is collected from healthy volunteers and preincubated for 30minutes. Next, cytokine such as IL-2 or IL-6 is added to the mixture andincubated for 15 minutes. Cytokines can be purchased, for example, fromPeproTech Inc. Cytokines are added to mixture at 100 ng/mL as finalconcentration. The mixture including the blood cells are hemolyzed,fixed, permeabilized, washed, and resuspended in stain buffer. BDCytofix/Cytoperm® solution (manufactured by Becton, Dickinson andCompany (BD)), for example, can be used to hemolyze, fix, andpermeabilize. Staining buffer (manufactured by BD), for example, can beused as stain buffer according to each protocol issued by BD.Fluorescence-labeled anti-phosphorylated STAT antibody andfluorescence-labeled anti-CD3 antibody are added to the cell suspensionand incubated for 30 minutes. Then, cells are washed and resuspended instain buffer. Fluorescence-labeled anti-phosphorylated STAT antibody andfluorescence-labeled anti-CD3 antibody can be purchased, for examplefrom BD, and final concentration of antibodies can be determinedaccording to each protocols issued by BD. Fluorescence intensity offluorescence-labeled cells in cell suspension is detected byflow-cytometory. Because the detected fluorescence intensity isproportional to the concentration of the phosphorylated STAT protein inCD3 positive cells, inhibitory activity against STAT phosphorylation bythe compounds can be calculated from the ratio between the abovementioned fluorescence intensity and the blank fluorescence intensitywhich is measured simultaneously without the compounds. From the plot oflogarithm of the compound concentrations and the inhibitory activities,the IC₅₀ value can be calculated.

Assay Example^(a) 3 Inhibition of Proliferation of Erythro-Leukemic CellLine

The inhibitory activity of the tricyclic pyrimidine compounds of thepresent invention on cell proliferation mediated by JAK signal can beassayed using a human erythro-leukemic cell line, TF-1.

TF-1 cells can be purchased from ATCC (American Type CultureCollection). TF-1 cells can be expanded in RPMI1640 media containing 5%FBS and 1 ng/mL GM-CSF (Granulocyte Macrophage Colony-StimulatingFactor) using a CO₂ incubator (5% CO₂, 37° C.). At the assay, TF-1 cellswashed by PBS (Phosphate Buffered Saline) are resuspended in RPMI1640media containing 5% FBS, and dispensed in 96-well culture plate at 1×10⁴cells/well. Compounds at various concentrations are added to the cellsand preincubated for 30 minutes, and then cytokine such as IL-4 or IL-6is added to the cells. Culture plates are incubated using a CO₂incubator (5% CO₂, 37° C.) for 3 days. Cell proliferation can be assayedusing WST-8 reagent (Kishida Chemical Co., Ltd.) according toinstructions by the manufacturer. The formazan pigment is generated bythe addition of WST-8 reagent solution to each well of the cultureplates and the subsequent incubation in a CO₂ incubator (5% CO₂, 37° C.)for 4 hours, and then detected by measuring the absorbance at 450 nmwith a microplate reader. From the plot of logarithm of the compoundconcentrations and the inhibitory activities, the IC₅₀ value can becalculated.

Reference Synthetic Example^(b) 1 Methyl 4-methylpyridin-3-ylcarbamate

Potassium tert-butoxide (10.3 g, 92.5 mmol) in tetrahydrofuran (25 mL)was stirred at 23 to 27° C. for 30 minutes, and dimethyl carbonate (4.67mL, 55.5 mmol) was added while the temperature was kept at 35° C. orbelow. To the reaction mixture, 3-amino-4-methylpyridine (5.00 g, 46.2mmol) in tetrahydrofuran (40 mL) stirred at 32 to 38° C. for 90 minuteswas added dropwise at 20 to 35° C. over 2 hours with stirring. Theresulting reaction mixture was cooled to 15 to 20° C., stirred withwater (25 mL) at 25° C. or below for 1 hour and extracted withtetrahydrofuran. The organic layer was azeotropically distilled withtoluene under reduced pressure to a volume of about 50 mL and stirred at23 to 27° C. for one day. The precipitated solid was collected byfiltration, washed with toluene and dried under reduced pressure to givethe title compound as a brown solid (6.77 g, yield 88%).

Reference Synthetic Example^(b) 2 Methylrac-(3R,4R)-1-benzyl-4-methylpiperidin-3-ylcarbamate

Methyl 4-methylpyridin-3-ylcarbamate (30.6 g, 184 mmol) and 5%rhodium-carbon (12 g) in acetic acid (120 mL) were stirred at 72 to 78°C. under a hydrogen atmosphere (70-80 psi). After disappearance of thestarting materials was confirmed by NMR, the reaction mixture wasfiltered, and the filtrate was concentrated under reduced pressure togive a concentrate (40.9 g). The concentrate (31.7 g) was stirred withbenzaldehyde (21.5 mL, 202 mmol) in toluene (184 mL) at 20 to 30° C. for30 minutes. The resulting toluene solution was added dropwise at 30° C.or below to a toluene (40 mL) solution of sodium triacetoxyborohydride(9.35 g, 44.0 mmol) stirred at 20 to 30° C. for 1 hour. The resultingreaction mixture was stirred for 2 hours, adjusted to pH 6-7 with 3 Maqueous sodium hydroxide at 20° C. to 30° C. and extracted with toluene.The organic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give a brown oil (38.1 g)containing the title compound. The oil was used for the next stepwithout further purification.

Reference Synthetic Example^(b) 3rac-(3R,4R)-1-Benzyl-4-methylpiperidin-3-amine

Crude methyl rac-(3R,4R)-1-benzyl-4-methylpiperidin-3-ylcarbamate (2.3g) in concentrated hydrochloric acid (15 mL) was refluxed for one dayunder heating and allowed to cool to room temperature. The hydrochloricacid was removed under reduced pressure, and the reaction mixture waspartitioned between chloroform and saturated aqueous sodium chloride.The aqueous layer was basified with saturated aqueous sodium carbonateand extracted with ethyl acetate twice, and the organic layers werecombined, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The resulting brown oil (4.94 g) containing the titlecompound was used for the next step without further purification.

Reference Synthetic Example^(b) 4 1H-Pyrrolo[2,3-b]pyridine 7-oxide

m-Chloroperbenzoic acid (25 wt % water content, 12.7 g, 55.2 mmol) inethyl acetate (30 mL) was gradually added dropwise to1H-pyrrolo[2,3-b]pyridine (5.14 g, 43.5 mmol) in ethyl acetate (45 mL)cooled to 0° C., and the reaction mixture was stirred at roomtemperature for one day and then stirred with m-chloroperbenzoic acid(25 wt % water content, 3.93 g, 17.1 mmol) in ethyl acetate (4 mL) atroom temperature for 4 hours. The reaction mixture was cooled with iceand filtered, and the resulting solid was purified by silica gel columnchromatography (silica gel NH type manufactured by Fuji Silysia ChemicalLtd.: chloroform/methanol=10/1 (v/v)) to give the title compound as ayellow solid (4.95 g, yield 85%).

Reference Synthetic Example^(b) 5 4-Chloro-1H-pyrrolo[2,3-b]pyridine

1H-Pyrrolo[2,3-b]pyridine 7-oxide (4.95 g, 36.9 mmol) inN,N-dimethylformamide (10 mL) was heated to 50° C., mixed withmethanesulfonyl chloride (8.00 mL, 103 mmol) and stirred at 73° C. for 3hours. The reaction mixture was cooled with ice and diluted with water(70 mL), neutralized with sodium hydroxide and stirred for 10 minutesunder cooling with ice. The precipitated solid was collected byfiltration, washed with water and dried under reduced pressure to givethe title compound as a reddish brown solid (4.65 g, yield 83%).

Reference Synthetic Example^(b) 64-Chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine

4-Chloro-1H-pyrrolo[2,3-b]pyridine (2.84 g, 18.6 mmol) inN,N-dimethylformamide (10 mL) and tetrahydrofuran (10 mL) was stirredwith sodium hydride (55 wt % dispersion in mineral oil, 1.08 g, 27.0mmol) under cooling with ice for 1 hour. The reaction mixture wasstirred with triisopropylsilyl chloride (6.0 mL, 28 mmol) at roomtemperature for one day. After addition of water, the reaction mixturewas warmed to room temperature and extracted with hexane twice. Theresulting organic layers were combined, washed with saturated aqueoussodium chloride dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane) to give the title compound as a reddish brownoil (5.74 mg, yield 99%).

Reference Synthetic Example^(b) 74-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

s-Butyllithium-hexane/cyclohexane solution (1.06 M, 27 mL, 29 mmol) wasadded to 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (5.74g, 18.6 mmol) in tetrahydrofuran (50 mL) cooled to −78° C., and thereaction mixture was stirred for 1 hour. The reaction mixture wasstirred with N,N-dimethylformamide (7.0 mL, 90 mmol) for another 1 hourand then with 4 M hydrogen chloride-1,4-dioxane solution (20 mL) for 30minutes, and after addition of water, extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The resulting residue was dissolved in dichloromethane (15 mL)and stirred with trifluoroacetic acid (15 mL) for one day. The reactionmixture was concentrated under reduced pressure, diluted with water andneutralized with saturated aqueous sodium hydrogen carbonate, and theresidue was collected by filtration and dried under reduced pressure.The crude product was mixed with ethyl acetate (20 mL) and hexane (20mL), and the solid was collected by filtration, washed with hexane anddried under reduced pressure to give the title compound as a pale yellowsolid (2.72 g, yield 81%).

Reference Synthetic Example^(b) 84-(Cyclohexylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (845 mg, 4.68 mmol)and cyclohexylamine (2.5 mL, 22 mmol) in ethylene glycol (2 mL) werestirred at 170° C. for 1 hour under microwave irradiation. The reactionmixture was allowed to cool to room temperature and, after addition ofwater, extracted with chloroform. The organic layer was stirred with 2 Mhydrochloric acid (20 mL) for 1 hour, and the organic layer wasseparated. The aqueous layer was adjusted to pH 9 or above with 10 Maqueous sodium hydroxide and extracted with chloroform. The organiclayers were combined, washed with saturated aqueous sodium chloride,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(chloroform/methanol=10/1 (v/v)) to give the title compound as a paleyellow oil (804 mg, yield 71%).

Reference Synthetic Example^(b) 94-(Cyclohexylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

4-(Cyclohexylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (273 mg,1.12 mmol) in N,N-dimethylformamide (3 mL) was stirred with sodiumhydride (55 wt % dispersion in mineral oil, 61.2 mg, 1.53 mmol) for 1hour under cooling with ice. The reaction mixture was stirred with[2-(chloromethoxy)ethyl]trimethylsilane (260 μL, 1.47 mmol) at roomtemperature for one day, and after addition of water, extracted withethyl acetate. The organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=5/1 (v/v)) to give the titlecompound as a pale yellow oil (265 mg, yield 63%).

Reference Synthetic Example^(b) 10(4-(Cyclohexylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol

4-(Cyclohexylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(104 mg, 0.279 mmol) in methanol (3 mL) was stirred with sodiumborohydride (15.8 mg, 0.418 mmol) at room temperature for 2 hours, afteraddition of water, the reaction mixture was extracted with chloroformtwice, and the organic layers were combined, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The resultingpale yellow oil containing the title compound was used for the next stepwithout further purification.

Reference Synthetic Example^(b) 111-Cyclohexyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-1,2,4,7-tetrahydropyrrolo[3′,2′:5,6]pyrido[4,3-d][1,3]oxazine

[4-(Cyclohexylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol(38 mg, 0.10 mmol) and aqueous formaldehyde (35 wt %, 0.6 mL, 8 mmol) inethanol (2 mL) were stirred at 75° C. for 1 hour. The reaction mixturewas then stirred with acetic acid (1 mL) at 75° C. for 1 hour, allowedto cool to room temperature, and after addition of saturated aqueoussodium hydrogen carbonate, extracted with ethyl acetate. The organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=2/1 (v/v)) to give the titlecompound as a colorless oil (19.8 mg, yield 51%).

Reference Synthetic Example^(b) 125-(Aminomethyl)-N-cyclohexyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine

(4-(Cyclohexylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol(870 mg, 2.31 mmol) obtained in Reference Synthetic Example^(b) 10,phthalimide (681 mg, 4.63 mmol) and triphenylphosphine (1.21, 4.63 mmol)in tetrahydrofuran (10 mL) were stirred at room temperature for 30minutes and then stirred with diisopropyl azodicarboxylate (936 mg, 4.63mmol) for one day. The reaction mixture was concentrated under reducedpressure, and after addition of water, extracted with ethyl acetate. Theorganic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=10/1 (v/v)) to removetriphenylphosphine oxide. The resulting crude product was dissolved inethanol (30 mL) and stirred with hydrazine monohydrate (1.0 mL, 12 mmol)at 80° C. for 1 hour and allowed to cool to room temperature. Theprecipitated solid was collected by filtration and washed with ethanoland chloroform. The filtrate and the washings were combined andconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (chloroform/methanol=20/1 (v/v) to givethe title compound as a colorless oil (513 mg, yield 59%).

Reference Synthetic Example^(b) 131-Cyclohexyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-3,4-dihydro-1H-Pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one

5-(Aminomethyl)-N-cyclohexyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine(127 mg, 0.339 mmol) in dichloromethane was stirred with1,1′-carbonyldiimidazole (65.9 mg, 0.407 mmol) at 60° C. for 2 hours.The reaction mixture was concentrated under reduced pressure and, afteraddition of water, extracted with chloroform. The organic layer wasdried over anhydrous magnesium sulfate and concentrated under reducedpressure to give the title compound as a colorless oil (93.2 mg, yield69%).

Reference Synthetic Example^(b) 141-Cyclohexyl-1,4-dihydro-7-{[2-(trimethylsilyl)ethoxy]methyl}-pyrrolo[3′,2′:5,6]pyrido[3,4-e]pyrimidine

5-(Aminomethyl)-N-cyclohexyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine(104 mg, 0.278 mmol) obtained in Reference Synthetic Example^(b) 12 inethyl orthoformate (1 mL) was reacted at 180° C. for 30 minutes undermicrowave irradiation and allowed to cool to room temperature. Afteraddition of water, the reaction mixture was extracted with ethylacetate, and the organic layer was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography (Hi Flash column aminotype manufactured by Yamazen Corporation: hexane/ethyl acetate=1/1 (v/v)to give the title compound as a pale yellow oil (48.8 mg, yield 45%).

Reference Synthetic Example^(b) 15 2,3-Dihydro-1H-pyrrolo[2,3-b]pyridine

1H-Pyrrolo[2,3-b]pyridine (8.78 g, 74.3 mmol) and 5% palladium-carbon ina mixture of triethylamine (5 mL) and formic acid (30 mL) was stirred at80° C. for 4 days. The reaction mixture was allowed to cool to roomtemperature and filtered, and the filtrate was concentrated underreduced pressure. The resulting residue was adjusted to pH 12 with 6 Maqueous sodium hydroxide and stirred at 65° C. for 5 hours. The reactionmixture was allowed to cool to room temperature and extracted withchloroform, and the organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=1/2→ethyl acetate/methanol=20/1 (v/v)) to give the titlecompound as a pale yellow solid (2.15 g, yield 24%).

Reference Synthetic Example^(b) 165-Bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

2,3-Dihydro-1H-pyrrolo[2,3-b]pyridine (4.40 g, 36.6 mmol) in a mixtureof pyridine (4.4 mL) and dichloromethane (20 mL) was gradually addeddropwise to bromine (7.00 g, 43.8 mmol) in dichloromethane (20 mL)cooled to 0° C., and the resulting reaction mixture was stirred at 0° C.for 20 minutes, after addition of saturated aqueous sodium thiosulfate,the reaction mixture was extracted with chloroform, and the organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=1/1→0/1 (v/v)) to give the titlecompound as a brown solid (2.83 g, yield 39%).

Reference Synthetic Example^(b) 17 5-Bromo-1H-pyrrolo[2,3-b]pyridine

5-Bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (2.83 g, 14.2 mol) andmanganese dioxide (5.0 g, 58 mmol) in chloroform (30 mL) were stirred at65° C. for 3 hours. The reaction mixture was allowed to cool to roomtemperature and filtered, and the solid was washed with chloroform, andthe filtrate and the washings were combined and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate/chloroform=2/1/1→1/1/0 (v/v/v)) togive the title compound as a brown solid (2.14 g, yield 76%).

Reference Synthetic Example^(b) 18 5-Bromo-1H-pyrrolo[2,3-b]pyridine7-oxide

m-Chloroperbenzoic acid (25 wt % water content, 322 mg, 1.40 mmol) inethyl acetate (5 mL) was gradually added dropwise to5-bromo-1H-pyrrolo[2,3-b]pyridine (184 mg, 0.934 mmol) in ethyl acetate(10 mL), and the reaction mixture was stirred at room temperature for 6hours. After addition of saturated aqueous sodium hydrogen carbonate,the reaction mixture was extracted with chloroform, and the organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was mixed with a mixture of ethylacetate/hexane=1/1 (v/v), and the solid was collected by filtration,washed with hexane and dried under reduced pressure to give the titlecompound as a light brown solid (150 mg, yield 75%).

Reference Synthetic Example^(b) 195-Bromo-4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine

5-Bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide (150 mg, 0.704 mmol) inN,N-dimethylformamide (2 mL) was heated to 50° C. and stirred withmethanesulfonyl chloride (58 μL, 0.75 mmol) at 70° C. for 2 hours andallowed to cool to room temperature. After addition of saturated aqueoussodium chloride, the reaction mixture was extracted with ethyl acetate,and the organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The resulting residue was dissolvedin N,N-dimethylformamide (2 mL), cooled to 0° C., mixed with sodiumhydride (55 wt % dispersion in mineral oil, 45 mg, 1.03 mmol) and[2-(chloromethoxy)ethyl]trimethylsilane (186 μL, 1.05 mmol) and stirredat room temperature for 3 hours. After addition of saturated aqueoussodium chloride, the reaction mixture was extracted with ethyl acetate,and the organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=20/1 (v/v)) to give thetitle compound as a pale yellow oil (158 mg, yield 62%).

Reference Synthetic Example^(b) 205-Bromo-N-cyclohexyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine

5-Bromo-4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine(150 mg, 0.415 mmol) and cyclohexylamine (1 mL, 9 mmol) in ethyleneglycol (1 mL) were stirred at 200° C. for 2 hour under microwaveirradiation. The reaction mixture was allowed to cool to roomtemperature and, after addition of saturated aqueous sodium chloride,extracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate=10/1(v/v)) to give the title compound as an orange oil (141 mg, yield 80%).

Reference Synthetic Example^(a) 211-(4-(Cyclohexylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone

5-Bromo-N-cyclohexyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine(160 mg, 0.377 mmol) in toluene (3 mL) was stirred withbis(triphenylphosphine)palladium (II) dichloride (35 mg, 0.050 mmol) andtributyl(1-ethoxyvinyl)tin (382 μL, 1.13 mmol) at 75° C. for 3 hours.The reaction mixture was allowed to cool to room temperature and stirredwith 1 M hydrochloric acid (2 mL) and potassium fluoride (100 mg, 1.73mmol) at room temperature for 30 minutes. The reaction mixture wasfiltered, and the solid was washed with ethyl acetate. The filtrate andthe washings were mixed with water and extracted with ethyl acetate, andthe organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=20/1→5/1 (v/v)) to givethe title compound as a yellow oil (58 mg, yield 40%).

Reference Synthetic Example^(a) 221-(4-(Cyclohexylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanol

1-(4-(Cyclohexylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone(13 mg, 0.034 mmol) in methanol (1 mL) was stirred with sodiumborohydride (30 mg, 0.79 mmol) at room temperature for 1 hour and at 60°C. for another 5 hours. The reaction mixture was allowed to cool to roomtemperature and, after addition of water, extracted with ethyl acetate,and the organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=4/1→3/1 (v/v)) to givethe title compound as a colorless oil (9.1 mg, yield 70%).

Reference Synthetic Example^(b) 231-Cyclohexyl-4-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-1,2,4,7-tetrahydropyrrolo[3′,2′:5,6]pyrido[4,3-d][1,3]oxazine

1-(4-(Cyclohexylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanol(9 mg, 0.02 mmol) and aqueous formaldehyde (35 wt %, 0.3 mL, 4 mmol) inethanol (1 mL) were stirred at 75° C. for 1 hour. The reaction mixturewas allowed to cool to room temperature and, after addition of water,extracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure. The resultingpale yellow oil (9 mg) containing the title compound was used for thenext step without further purification.

Reference Synthetic Example^(b) 241-Cyclohexyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

1-(4-(Cyclohexylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone(25 mg, 0.065 mmol) obtained in Reference Synthetic Example^(b) 21 inN,N-dimethylformamide dimethyl acetal (0.5 mL) was stirred at 180° C.for 3 hours under microwave irradiation. The reaction mixture wasallowed to cool to room temperature and concentrated under reducedpressure, and the resulting residue was dissolved in tetrahydrofuran (1mL) and stirred with 1 M hydrochloric acid (1 mL) at 80° C. for 1 hour.The reaction mixture was allowed to cool to room temperature and, afteraddition of saturated aqueous sodium hydrogen carbonate, extracted withchloroform, and the organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate/methanol=1/1/0→0/10/1 (v/v/v)) to give the title compound as acolorless oil (13.6 mg, yield 53%).

Reference Synthetic Example^(b) 254-Chloro-5-(methylsulfonyl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine

s-Butyllithium-hexane/cyclohexane solution (1.06 M, 0.700 mL, 0.742mmol) was gradually added dropwise to4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.324mmol) obtained in Reference Synthetic Example^(b) 6 in tetrahydrofuran(1 mL) cooled to −78° C., and the reaction mixture was stirred at −78°C. for 30 minutes and stirred with dimethyl disulfide (30 μL, 0.33 mmol)at −78° C. for 30 minutes. After addition of 1 M aqueous sodiumhydroxide, the reaction mixture was extracted with ethyl acetate, andthe organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The resulting residue was dissolvedin ethanol (2 mL) and stirred with ammonium molybdate tetrahydrate (40mg, 0.032 mmol) and aqueous hydrogen peroxide (30 wt %, 132 μL, 1.29mmol) at room temperature for 5 hours. After addition of water, thereaction mixture was extracted with ethyl acetate, and the organic layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate=20/1→5/1 (v/v)) to give the title compound as apale yellow oil (61.4 mg, yield 49%).

Reference Synthetic Example^(b) 26N-Cyclohexyl-5-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

4-Chloro-5-(methylsulfonyl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine(61 mg, 0.16 mmol) in cyclohexylamine (200 μL, 1.74 mmol) was stirredwith N,N-diisopropylethylamine (40 μL, 0.23 mmol) at 120° C. for 30minutes The reaction mixture was allowed to cool to room temperatureand, after addition of water, extracted with chloroform, and the organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=20/1→5/1 (v/v)) to give the titlecompound as a colorless solid (7.0 mg, yield 15%).

Reference Synthetic Example^(b) 27N-Cyclohexyl-5-(methylsulfonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine

N-Cyclohexyl-5-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (7.0mg, 0.024 mmol) in N,N-dimethylformamide (1 mL) was stirred with sodiumhydride (55 wt % dispersion in mineral oil, 3.0 mg, 0.069 mmol) and[2-(chloromethoxy)ethyl]trimethylsilane (10 μL, 0.057 mmol) at roomtemperature for 2 hours. After addition of saturated aqueous sodiumchloride, the reaction mixture was extracted with ethyl acetate, and theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=10/1→3/1 (v/v)) to give the titlecompound as a colorless oil (6.1 mg, yield 60%).

Reference Synthetic Example^(b) 281-Cyclohexyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydropyrrolo[3′,2′: 5,6]pyrido[3,4-b][1,4]thiazine-4,4(7H)-dione

N-Cyclohexyl-5-(methylsulfonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine(6.1 mg, 0.014 mmol) in N,N-dimethylformamide dimethyl acetal (2.5 mL)was stirred at 170° C. for 3 hours under microwave irradiation. Thereaction mixture was allowed to cool to room temperature andconcentrated under reduced pressure. The resulting residue was dissolvedin tetrahydrofuran (1 mL) and stirred with 1 M hydrochloric acid (1 mL)at 80° C. for 1 hour. The reaction mixture was allowed to cool to roomtemperature and, after addition of water, extracted with ethyl acetate,and the organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The resulting pale yellow oil (8.5mg) containing the title compound was used for the next step withoutfurther purification.

Reference Synthetic Example^(b) 294-(Cyclohexylamino)-1{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid

4-(Cyclohexylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(380 mg, 1.02 mmol) obtained in Reference Synthetic Example^(b) 9 inacetic acid (4 mL) was stirred with sulphamic acid (150 mg, 1.54 mmol)and 2-methyl-2-butene (500 μL, 4.71 mmol) under cooling with ice, andthen sodium chlorite (100 mg, 1.11 mmol) in water (0.5 mL) was addeddropwise, and the resulting reaction mixture was stirred at roomtemperature for 1 hour. Sodium chlorite (30 mg, 0.33 mmol) in water (0.3mL) was further added dropwise, and the resulting reaction mixture wasstirred for 1 hour. After addition of water, the reaction mixture wasextracted with chloroform, and the organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=3/1→0/1 (v/v)) to give the title compound as a pale yellow oil(207 mg, yield 52%).

Reference Synthetic Example^(b) 304-(Cyclohexylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

4-(Cyclohexylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid (100 mg, 0.257 mmol) in dichloromethane (2 mL) was stirred with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10 mg,0.052 mmol), N-hydroxybenzotriazole (50 mg, 0.37 mmol) and 7 Mammonia-methanol solution (0.2 mL, 1.4 mmol) at room temperature for oneday. After addition of saturated aqueous ammonium chloride, the reactionmixture was extracted with chloroform, and the organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(hexane/ethyl acetate=1/1→0/1 (v/v)) to give the title compound as apale yellow amorphous (71.1 mg, yield 71%).

Reference Synthetic Example^(b) 314-(Cyclohexylamino)-N-formyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

4-(Cyclohexylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide(45 mg, 0.12 mmol) in triethyl orthoformate (2 mL) was stirred at 120°C. for one day. The reaction mixture was allowed to cool to roomtemperature and concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (hexane/ethylacetate=3/1→0/1 (v/v)) to give the title compound as a pale yellowamorphous (12.4 mg, yield 27%).

Reference Synthetic Example^(b) 321-Cyclohexyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-4(7H)-one

4-(Cyclohexylamino)-N-formyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide(12.4 mg, 0.0311 mmol) in N-methyl-2-pyrrolidinone (0.5 mL) was stirredat 200° C. for 30 minutes under microwave irradiation. The reactionmixture was allowed to cool to room temperature and, after addition ofsaturated aqueous ammonium chloride, extracted with ethyl acetate, andthe organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give thetitle compound as a pale yellow amorphous (9.2 mg, yield 74%).

Reference Synthetic Example^(b) 331-(4-Chloro-1{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone

5-Bromo-4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine(47 mg, 0.13 mmol) obtained in Reference Synthetic Example^(b) 19 intoluene (1 mL) was stirred with bis(triphenylphosphine)palladium (II)dichloride (10 mg, 0.014 mmol) and tributyl(1-ethoxyvinyl)tin (50 μL,0.15 mmol) at 120° C. for 4 hours. The reaction mixture was allowed tocool to room temperature and stirred with water (2 mL) and potassiumfluoride (100 mg, 1.73 mmol) at room temperature for 1 hour. Thereaction mixture was filtered, and the solid was washed with ethylacetate. The filtrate and the washings were mixed with water andextracted with ethyl acetate, and the organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was stirred withhydrogen chloride-methanol solution (10 wt %, 0.1 mL) at roomtemperature for 10 minutes. The reaction mixture was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography (hexane/ethyl acetate=10/1→2/1 (v/v)) to give the titlecompound as a pale yellow oil (20 mg, yield 47%).

Reference Synthetic Example^(b) 34rac-1-(4-{[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone

1-(4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone(15 mg, 0.46 mmol) and rac-(3R,4R)-1-benzyl-4-methylpiperidin-3-amine(34 mg, 0.17 mmol) obtained in Reference Synthetic Example^(b) 3 inethylene glycol (3 mL) was stirred with N,N-diisopropylethylamine (10μL, 0.057 mmol) at 200° C. for 1 hour under microwave irradiation. Thereaction mixture was allowed to cool to room temperature and stirredwith methanol (2 mL) and 1 M hydrochloric acid (1 mL) at 50° C. for 30minutes. The reaction mixture was allowed to cool to room temperatureand, after addition of saturated aqueous sodium hydrogen carbonate,extracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=10/1→4/1 (v/v)) to give the title compound as a yellow oil (7.0mg, yield 31%).

Reference Synthetic Example^(b) 35rac-1-[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

rac-1-(4-{[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone(20 mg, 0.041 mmol) in N,N-dimethylformamide dimethyl acetal (1 mL) wasstirred at 170° C. for 6 hours under microwave irradiation. The reactionmixture was allowed to cool to room temperature and concentrated underreduced pressure, and the resulting residue was dissolved intetrahydrofuran (1 mL) and stirred with 1 M hydrochloric acid (1 mL) at80° C. for 1 hour. The reaction mixture was allowed to cool to roomtemperature and, after addition of saturated aqueous sodium hydrogencarbonate, extracted with chloroform, and the organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(hexane/ethyl acetate/methanol=1/1/0→0/5/1 (v/v/v)) to give the titlecompound as a yellow oil (6.1 mg, yield 30%).

Reference Synthetic Example^(b) 36rac-1-[(3R,4R)-4-Methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

rac-1-[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(98 mg, 0.20 mmol) and 5% palladium-carbon (65 mg) in methanol (2 mL)were stirred at room temperature for 2 hours under a hydrogenatmosphere, then at 40° C. for 5 hours and at room temperature for oneday. The reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure to give the title compound as a paleyellow amorphous (76.8 mg, yield 95%).

Reference Synthetic Example^(b) 37rac-1-[(3R,4R)-1-(Isobutylsulfonyl)-4-methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

rac-1-[(3R,4R)-4-Methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(23 mg, 0.056 mmol) in dichloromethane (2 mL) was mixed withN,N-diisopropylethylamine (30 μL, 0.17 mmol) and2-methylpropane-1-sulfonyl chloride (12 μL, 0.092 mmol) under coolingwith ice and stirred at room temperature for 2 hours. After addition ofwater, the reaction mixture was extracted with ethyl acetate, and theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate/methanol=1/1/0→0/10/1 (v/v/v)) togive the title compound as a pale pink solid (18.3 mg, yield 62%).

Reference Synthetic Example^(b) 38rac-4-{[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (247 mg, 1.36 mmol)obtained in Reference Synthetic Example^(b) 7 andrac-(3R,4R)-1-benzyl-4-methylpiperidin-3-amine (700 mg, 3.42 mmol)obtained in Reference Synthetic Example^(b) 3 in ethylene glycol (3 mL)were stirred at 180° C. for 3 hours under microwave irradiation. Thereaction mixture was allowed to cool to room temperature and, afteraddition of water and 1 M aqueous sodium hydroxide, extracted withchloroform, and the organic layer was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The resulting residuewas stirred with 1,4-dioxane (5 mL), 4 M hydrogen chloride-1,4-dioxanesolution (10 mL) and water (2 mL) at room temperature for one day. Thereaction mixture was concentrated under reduced pressure, adjusted to pH9 or above with 1M aqueous sodium hydroxide and extracted withchloroform and water, and the organic layer was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (Hi Flash column aminotype manufactured by Yamazen Corporation: hexane/ethyl acetate=1/1(v/v)) to give the title compound as a brown oil (154 mg, yield 33%).

Reference Synthetic Example^(b) 39rac-4-{[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

rac-4-{[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(118 mg, 0.338 mmol) in N,N-dimethylformamide (3 mL) was cooled to 0° C.and stirred with sodium hydride (55 wt % dispersion in mineral oil, 126mg, 0.586 mmol) for 30 minutes and then with[2-(chloromethoxy)ethyl]trimethylsilane (104 μL. 0.586 mmol) at roomtemperature for one day. After addition of water, the reaction mixturewas extracted with chloroform, and the organic layer was dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=1/1 (v/v)) to give the title compound as a brown oil (67.5 mg,yield 42%).

Reference Synthetic Example^(b) 40rac-(4-{[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol

rac-4-{[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(112 mg, 0.234 mmol) in methanol was stirred with sodium borohydride(13.3 mg, 0.351 mmol) at room temperature for 1 hour. The reactionmixture was concentrated under reduced pressure and, after addition ofwater, extracted with ethyl acetate, and the organic layer was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(Hi Flash column amino type manufactured by Yamazen Corporation:hexane/ethyl acetate=1/1 (v/v)) to give the title compound as acolorless oil (55 mg, yield 49%).

Reference Synthetic Example^(b) 41rac-1-[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1,2,4,7-tetrahydropyrrolo[3′,2′:5,6]pyrido[4,3-d][1,3]oxazine

rac-(4-{[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol(55 mg, 0.11 mmol) was stirred with formic acid (2 mL) and acetic acid(200 μL) at 75° C. for 4 hours. The reaction mixture was concentratedunder reduced pressure and, after addition of water, extracted withchloroform, and the organic layer was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate=2/1(v/v)) to give the title compound (34.3 mg, yield 61%).

Reference Synthetic Example^(b) 42 6-Bromo-3H-imidazo[4,5-b]pyridine

2,3-Diamino-5-bromopyridine (4.10 g, 21.8 mmol) in formic acid (25 mL)was stirred at 100° C. for 4 hours. The reaction mixture was allowed tocool to room temperature and concentrated under reduced pressure, andthe resulting residue was mixed with water and adjusted to pH 8 or abovewith saturated aqueous sodium hydrogen carbonate. The precipitated solidwas collected by filtration, washed with water and chloroform and driedunder reduced pressure to give the title compound as a dark brown solid(4.13 g, yield 96%).

Reference Synthetic Example^(b) 43 6-Bromo-3H-imidazo[4,5-b]pyridine4-oxide

m-Chloroperbenzoic acid (25 wt % water content, 2.77 g, 12.0 mmol) wasgradually added dropwise to 6-bromo-3H-imidazo[4,5-b]pyridine (1.58 mg,7.98 mmol) in ethyl acetate (15 mL), and the reaction mixture wasstirred at room temperature for one day. The precipitated solid wascollected by filtration and washed with ethyl acetate and diethyl etherand dried under reduced pressure to give the title compound as a paleyellow solid (1.67 g, yield 98%).

Reference Synthetic Example^(b) 446-Bromo-7-chloro-3H-imidazo[4,5-b]pyridine

6-Bromo-3H-imidazo[4,5-b]pyridine 4-oxide (1.88 g, 8.82 mmol) inN,N-dimethylformamide (12 mL) was heated to 50° C., mixed withmethansulfonyl chloride (8.00 mL, 103 mmol) and stirred at 73° C. for 3hours. The reaction mixture was cooled with ice and gradually pouredinto saturated aqueous sodium hydrogen carbonate (75 mL), and theprecipitated solid was collected by filtration, washed with water andchloroform and dried under reduced pressure to give the title compoundas a dark brown solid (1.07 g, yield 52%).

Reference Synthetic Example^(b) 456-Bromo-7-chloro-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridine

6-Bromo-7-chloro-3H-imidazo[4,5-b]pyridine (1.07 g, 4.60 mmol) inN,N-dimethylformamide (12 mL) was cooled to 0° C., mixed with sodiumhydride (55 wt % dispersion in mineral oil, 300 mg, 6.88 mmol) and[2-(chloromethoxy)ethyl]trimethylsilane (12.0 mL, 6.78 mmol) and stirredat room temperature for 3 hours. After addition of saturated aqueoussodium chloride, the reaction mixture was extracted with ethyl acetate,and the organic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane/ethyl acetate=10/1→5/1(v/v)) to give the title compound as a yellow oil (640 mg, yield 38%).

Reference Synthetic Example^(b) 461-(7-Chloro-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridin-6-yl)ethanone

6-Bromo-7-chloro-3-{[-2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridine(379 mg, 1.05 mmol) in toluene (6 mL) was stirred withbis(triphenylphosphine)palladium(II) dichloride (106 mg, 0.151 mmol) andtributyl(1-ethoxyvinyl)tin (435 mg, 1.21 mmol) at 120° C. 4 hours. Thereaction mixture was allowed to cool to room temperature and stirredwith water (20 mL) and potassium fluoride (0.5 g) at room temperaturefor 1 hour. The reaction mixture was extracted with ethyl acetate, andthe organic layer was dried over anhydrous magnesium sulfate andfiltered. The filtrate was stirred with hydrogen chloride-methanolsolution (10 wt %, 4 mL) at room temperature for 10 minutes. Thereaction mixture was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (hexane/ethylacetate=5/1→3/1 (v/v)) to give the title compound as a yellow solid(89.6 mg, yield 26%).

Reference Synthetic Example^(b) 471-[7-(Cyclohexylamino)-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridin-6-yl]ethanone

1-[7-Chloro-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridin-6-yl]ethanone(89.6 mg, 0.275 mmol) and cyclohexylamine (214 mg, 2.16 mmol) inethylene glycol (2 mL) were stirred at 180° C. for 1 hour undermicrowave irradiation. The reaction mixture was allowed to cool to roomtemperature and, after addition of saturated aqueous sodium chloride,extracted with chloroform. The organic layer was stirred with 2 Mhydrochloric acid (12 mL) at room temperature for 1 hour. The reactionmixture was basified with 10 M aqueous sodium hydroxide and extractedwith chloroform, and the organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography hexane/ethyl acetate=1/1 (v/v)) to give the titlecompound as a dark brown oil (88.9 mg, yield 83%).

Reference Synthetic Example^(b) 489-Cyclohexyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-h][1,6]naphthyridin-6(9H)-one

1-[7-(Cyclohexylamino)-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridin-6-yl]ethanone(88.9 mg, 0.229 mmol) in N,N-dimethylformamide dimethyl acetal (2.0 mL)was stirred at 180° C. for 5 hours. The reaction mixture was allowed tocool to room temperature and concentrated under reduced pressure, andthe resulting residue was dissolved in tetrahydrofuran (5 mL) andstirred with 1 M hydrochloric acid (2 mL) at 80° C. for 1 hour. Thereaction mixture was allowed to cool to room temperature and, afteraddition of saturated aqueous sodium hydrogen carbonate, extracted withethyl acetate, and the organic layer was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate/methanol=1/1/0→0/10/1 (v/v/v)) to give the title compound as ayellow solid (57.5 mg, yield 63%).

Reference Synthetic Example^(b) 491-(3-Bromo-4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone

1-(4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone(91 mg, 0.28 mmol) obtained in Reference Synthetic Example^(b) 33 indichloromethane (3 mL) was mixed with N-bromosuccinimide (75 mg, 0.42mmol) under cooling with ice and stirred at room temperature for 2hours. After addition of saturated aqueous sodium thiosulfate, thereaction mixture was extracted with ethyl acetate, and the organic layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate=5/1 (v/v)) to give the title compound as acolorless oil (61.0 mg, yield 54%).

Reference Synthetic Example^(b) 50rac-1-(4-{[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]amino}-3-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone

1-(3-Bromo-4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone(61 mg, 0.15 mmol) was stirred withrac-(3R,4R)-1-Benzyl-4-methylpiperidin-3-amine (85 mg, 0.42 mmol)obtained in Reference Synthetic Example^(b) 3 andN,N-diisopropylethylamine (50 μL, 0.29 mmol) at 130° C. for 5 hours. Thereaction mixture was allowed to cool to room temperature and purified bysilica gel column chromatography (hexane/ethyl acetate=10/1 (v/v)) togive the title compound as a pale yellow oil (28.7 mg, yield 33%).

Reference Synthetic Example^(b) 51rac-1-[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]-9-bromo-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4-(7H)-one

The reactions in Reference Synthetic Example^(b) 35 were carried out insubstantially the same manners except thatrac-1-(4-{[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]amino}-3-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanonewas used instead ofrac-1-(4-{[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanoneto give the title compound as a colorless oil (12.3 mg, yield 45%).

Reference Synthetic Example^(b) 521-(3,4-Dichloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone

1-(4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone(80 mg, 0.25 mmol) obtained in Reference Synthetic Example^(b) 33 inN,N-dimethylformamide (2 mL) was stirred with N-chlorosuccinimide (66mg, 0.49 mmol) at 80° C. for 3 hours. The reaction mixture was allowedto cool to room temperature and, after addition of saturated aqueoussodium chloride, extracted with ethyl acetate, and the organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate=10/1→5/1 (v/v)) to give the title compound as acolorless solid (23.8 mg, yield 27%).

Reference Synthetic Example^(b) 53rac-1-(4-{[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]amino}-3-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone

The reactions in Reference Synthetic Example^(b) 50 were carried out insubstantially the same manners except that1-(3,4-dichloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanonewas used instead of1-(3-bromo-4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanoneto give the title compound as a pale yellow oil (13.4 mg, yield 39%).

Reference Synthetic Example^(b) 54rac-1-[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]-9-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

The reactions in Reference Synthetic Example^(b) 35 were carried out insubstantially the same manners except thatrac-1-(4-{[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]amino}-3-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanonewas used instead ofrac-1-(4-{[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanoneto give the title compound as a colorless oil (5.6 mg, yield 42%).

Reference Synthetic Example^(b) 554-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (550 mg, 3.05 mmol)obtained in Reference Synthetic Example^(b) 7 in N,N-dimethylformamide(5 mL) was stirred with sodium hydride (60 wt % dispersion in liquidparaffin, 150 mg, 3.75 mmol) for 10 minutes under cooling with ice andthen stirred with [2-(chloromethoxy)ethyl]trimethylsilane (650 μL, 3.67mmol) at room temperature for 30 minutes. After addition of saturatedaqueous ammonium chloride, the reaction mixture was extracted with ethylacetate, and the organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=5/1 (v/v)) to give the titlecompound as a colorless solid (815 mg, yield 86%).

Reference Synthetic Example^(b) 561-(4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)propan-1-ol

4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(117 mg, 0.360 mmol) in tetrahydrofuran (2 mL) was mixed withethylmagnesium bromide-tetrahydrofuran solution (1.0 M, 1.0 mL, 1.0mmol) under cooling with ice and stirred at room temperature for oneday. After addition of saturated aqueous ammonium chloride, the reactionmixture was extracted with ethyl acetate, and the organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate=4/1 (v/v)) to give the title compound as acolorless oil (75.6 mg, yield 62%).

Reference Synthetic Example^(b) 571-(4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)propan-1-one

1-(4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)propan-1-ol(75.6 mg, 0.222 mmol) in 1,2-dimethoxyethane (5 mL) was vigorouslystirred with manganese dioxide (450 mg, 5.17 mmol) at 60° C. for 3 hoursand then at 80° C. for 3 hours. The reaction mixture was filtered, thesolid was washed with chloroform, and the filtrate and the washings wereconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=10/1→5/1 (v/v)) to givethe title compound as a colorless oil (39.9 mg, yield 53%).

Reference Synthetic Example^(b) 58rac-1-(4-{[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)propan-1-one

The reactions in Reference Synthetic Example^(b) 50 were carried out insubstantially the same manners except that1-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)propan-1-onewas used instead of1-(3-bromo-4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanoneto give the title compound as a pale yellow oil (40.1 mg, yield 71%).

Reference Synthetic Example^(b) 59rac-1-[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]-3-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

The reactions in Reference Synthetic Example^(b) 35 were carried out insubstantially the same manners except thatrac-1-(4-{[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)propan-1-onewas used instead ofrac-1-(4-{[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanoneto give the title compound as a colorless oil (18.0 mg, yield 44%).

Reference Synthetic Example^(b) 60rac-1-[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]-3-bromo-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

rac-1-[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(70 mg, 0.14 mmol) obtained in Reference Synthetic Example^(b) 35 indichloromethane (5 mL) was mixed with N-bromosuccinimide (25 mg, 0.14mmol) under cooling with ice and stirred at room temperature for one dayand then with N-bromosuccinimide (8 mg, 0.04 mmol) for one day. Afteraddition of saturated aqueous sodium hydrogen carbonate, the reactionmixture was extracted with ethyl acetate, and the organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate=5/1→2/1 (v/v)) to give a mixture (22.4 mg)containing the title compound. The mixture was used for the next stepwithout further purification.

Reference Synthetic Example^(b) 61rac-2-{[3R,4R)-4-Methyl-3-(4-oxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)piperidin-1-yl]sulfonyl}benzonitrile

rac-1-[(3R,4R)-4-Methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(20 mg, 0.049 mmol) obtained in Reference Synthetic Example^(b) 36 indichloromethane (2 mL) was stirred with 2-cyanobenzenesulfonyl chloride(15 mg, 0.074 mmol) and N,N-diisopropylethylamine (20 μL, 0.11 mmol) atroom temperature for 1 hour. The reaction mixture was purified by silicagel column chromatography (hexane/ethyl acetate/methanol=1/1/0→0/10/1(v/v/v)) to give the title compound as a colorless solid (24.5 mg, yield87%).

Reference Synthetic Examples^(b) 62 to 71

The reactions in Reference Synthetic Example^(b) 61 were carried out insubstantially the same manners except that 3-cyanobenzensulfonylchloride, ethyl chloroform ate, 1-isocyanato-2-(trifluoromethyl)benzene,1-isocyanato-3-(trifluoromethyl)benzene, 2-(trifluoromethyl)benzoylchloride, 3-(trifluoromethyl)lbenzoyl chloride, 2-(4-fluorophenyl)acetylchloride, 3-(trifluoromethyl)benzenesulfonyl chloride,4-(trifluoromethyl)benzoyl chloride or benzyl chloroformate was usedinstead of 2-cyanobenzenesulfonyl chloride to give the compounds ofReference Synthetic Examples^(b) 62 to 71. The names, morphologies andyields of the compounds synthesized are shown in Tables^(b) 3 to 4.

TABLE^(b) 3 Rf Compound Name Morphology Yield 62rac-3-{[(3R,4R)-4-methyl-3-(4-oxo- colorless 65%7-{[2-(trimethylsilyl)ethoxy]methyl}- solid4,7-dihydro-1H-pyrrolo[2,3-h][1, 6]naphthyridin-1-yl)piperidin-1-yl]sulfonyl}benzonitrile 63 rac-(3R,4R)-ethyl colorless 85%4-methyl-3-(4-oxo-7-{[2-(trimethylsilyl)ethoxy]methyl}- oil 4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin- 1-yl)piperidine-1-carboxylate 64rac-(3R,4R)-4-methyl-3-(4-oxo-7-{[2- colorless 87%(trimethylsilyl)ethoxy]methyl}- oil 4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)-N-[2-(trifluoromethyl)phenyl]piperidine-1-carboxamide 65 rac-(3R,4R)-4-methyl-3-(4-oxo-7-{[2- colorless 98%(trimethylsilyl)ethoxy]methyl}- oil 4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)-N-[3-(trifluoromethyl)phenyl]piperidine-1-carboxamide 66rac-1-{(3R,4R)-4-methyl-1-[2-(trifluoromethyl)benzoyl]piperidin-colorless 94% 3- oil yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin- 4(7H)-one 67rac-1-{(3R,4R)-4-methyl-1-[3-(trifluoromethyl)benzoyl]piperidin-colorless 92% 3- oil yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin- 4(7H)-one 68rac-1-{(3R,4R)-1-[2-(4-fluorophenyl)acetyl]- colorless 80%4-methylpiperidin-3-yl}- oil 7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin- 4(7H)-one 69rac-1-((3R,4R)-4-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}piperidin-colorless 78% 3-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}- oil1H-pyrrolo[2,3-h][1, 6]naphthyridin-4(7H)-one 70rac-1-{(3R,4R)-4-methyl-1-[4-(trifluoromethyl)benzoyl]piperidin-colorless 69% 3- oil yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin- 4(7H)-one

TABLE^(b) 4 Rf Compound Name Morphology Yield 71 rac-(3R,4R)-benzylcolorless 66% 4-methyl-3-(4-oxo-7-{[2-(trimethylsilyl)ethoxy] oilmethyl}-4,7-dihydro- 1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)piperidine-1-carboxylate

Reference Synthetic Example^(b) 72 Phenyl 1,3,4-thiadiazol-2-ylcarbamate

1,3,4-Thiadiazol-2-amine (253 mg, 2.50 mmol) in N,N-dimethylacetamide (3mL) was stirred with phenyl chloroformate (392 μL, 3.13 mmol) at roomtemperature for one day. Water was added to the reaction mixture, andthe precipitated solid was collected by filtration, washed with waterand hexane and dried under reduced pressure to give the title compoundas a colorless solid (418 mg, yield 76%).

Reference Synthetic Example^(b) 73rac-(3R,4R)-4-Methyl-3-(4-oxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)-N-(1,3,4-thiadiazol-2-yl)piperidine-1-carboxamide

rac-1-[(3R,4R)-4-Methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(30.2 mg, 0.0732 mmol) obtained in Reference Synthetic Example^(b) 36 intetrahydrofuran (3 mL) was refluxed with phenyl1,3,4-thiadizol-2-ylcarbamate (19.6 mg, 0.0886 mmol) and triethylamine(17.9 μL, 0.128 mmol) for 3 hours under heating. The reaction mixturewas concentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate→chloroform/methanol=10/1(v/v)) to give the title compound as a pale yellow solid (44.0 mg,quantitative yield).

Reference Synthetic Example^(b) 74Phenyl(3-methylisothiazol-5-yl)carbamate

3-Methylisothiazol-5-amine (156 mg, 1.04 mmol) in pyridine (1.2 mL) wasmixed with phenyl chloroformate (260 μL, 2.07 mmol) under cooling withice and stirred at room temperature for 3 hours. The reaction mixturewas concentrated under reduced pressure, and after addition of water,extracted with chloroform twice, and the organic layer was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=1/1 (v/v)) to give the titlecompound as a pale yellow solid (173 mg, yield 71%).

Reference Synthetic Example^(b) 75rac-(3R,4R)-4-Methyl-N-(3-methylisothiazol-5-yl)-3-(4-oxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)piperidine-1-carboxamide

rac-1-[(3R,4R)-4-Methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(29.5 mg, 0.0715 mmol) obtained in Reference Synthetic Example^(b) 36 intetrahydrofuran (3 mL) was refluxed withphenyl(3-methylthiazol-5-yl)carbamate (21.2 mg, 0.0905 mmol) andtriethylamine (17.5 μL, 0.125 mmol) for 3 hours under heating. Thereaction mixture was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (ethylacetate→chloroform/methanol=10/1 (v/v)) to give the title compound as ayellow oil (38.4 mg, yield 97%).

Reference Synthetic Example^(b) 76rac-1-[(3R,4R)-1-(Cyclopentanecarbonyl)-4-methylpiperidin-3-A-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

rac-1-[(3R,4R)-4-Methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(31.0 mg, 0.751 mmol) obtained in Reference Synthetic Example^(b) 36 andtriethylamine (30.0 μL, 0.215 mmol) in tetrahydrofuran (4 mL) werestirred with cyclopentanecarbonyl chloride (20.0 μL, 0.165 mmol) at roomtemperature for one day. After addition of 1 M aqueous sodium hydroxide,the reaction mixture was extracted with chloroform, and the organiclayer was washed with saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography(chloroform/methanol=10/1 v/v)) to give the title compound as a paleyellow oil (44.5 mg, quantitative yield).

Reference Synthetic Example^(b) 77rac-1-{(3R,4R)-4-methyl-1-[3-(trifluoromethyl)benzyl]piperidin-3-yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

rac-1-[(3R,4R)-4-Methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(24.8 mg, 0.0601 mmol) obtained in Reference Synthetic Example^(b) 36 intetrahydrofuran (4 mL) was stirred sodium hydride (55 wt % dispersion inmineral oil, 49.4 mg, 1.23 mmol) and 3-(trifluoromethyl)benzyl bromide(38.2 mg, 0.160 mmol) at room temperature for one day. After addition ofwater under cooling with ice, the reaction mixture was extracted withethyl acetate, and the organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate→chloroform/methanol=20/1 (v/v)) to givethe title compound as a pale yellow oil (26.8 mg, quantitative yield).

Reference Synthetic Example^(b) 78rac-1-{(3R,4R)-4-methyl-1-[4-(trifluoromethyl)benzyl]piperidin-3-yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

The reactions in Reference Synthetic Example^(b) 77 were carried out insubstantially the same manners except that 4-(trifluoromethyl)benzylbromide was used instead of 3-(trifluoromethyl)benzyl bromide to givethe title compound as a pale yellow oil (32.8 mg, quantitative yield).

Reference Synthetic Example^(b) 79rac-1-{(3R,4R)-4-methyl-1-[2-(trifluoromethyl)benzyl]piperidin-3-yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

rac-1-[(3R,4R)-4-Methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(13.4 mg, 0.0325 mmol) obtained in Reference Synthetic Example^(b) 36 intetrahydrofuran (4 mL) was stirred with sodium hydride (55 wt %dispersion in mineral oil, 30.6 mg, 0.765 mmol) and2-(trifluoromethyl)benzyl bromide (27.8 mg, 0.116 mmol) at roomtemperature for one day. After addition of water under cooling with ice,the reaction mixture was extracted with ethyl acetate, and the organiclayer was washed with saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate→chloroform/methanol=20/1 (v/v)) to give the title compound as apale yellow oil, which was used for the next step.

Reference Synthetic Example^(b) 80rac-3-{[(3R,4R)-4-Methyl-3-(4-oxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)piperidin-1-yl]methyl}benzonitrile

rac-1-[(3R,4R)-4-Methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(25.0 mg, 0.0606 mmol) obtained in Reference Synthetic Example^(b) 36 intetrahydrofuran (3 mL) was stirred with sodium hydride (55 wt %dispersion in mineral oil, 15.4 mg, 0.385 mmol) and 3-cyanobenzylbromide (12.8 mg, 0.0653 mmol) at room temperature for one day. Thereaction mixture was further stirred with sodium hydride (55 wt %dispersion in mineral oil, 20.8 mg, 0.520 mmol) and 3-cyanobenzylbromide (11.6 mg, 0.0592 mmol) at room temperature for one day. Afteraddition of water, the reaction mixture was extracted with chloroformtwice, and the organic layer was concentrated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate→chloroform/methanol=10/1 (v/v)) to give the title compound as apale yellow oil (32.4 mg, quantitative yield).

Reference Synthetic Example^(b) 81rac-2-{[(3R,4R)-4-Methyl-3-(4-oxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)piperidin-1-yl]methyl}benzonitrile

The reactions in Reference Synthetic Example^(b) 77 were carried out insubstantially the same manners except that 2-cyanobenzyl bromide wasused instead of 3-(trifluoromethyl)benzyl bromide to give the titlecompound as a pale yellow oil (31.4 mg, yield 97%).

Reference Synthetic Example^(b) 82rac-4-{[(3R,4R)-4-Methyl-3-(4-oxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)piperidin-1-yl]methyl}benzonitrile

The reactions in Reference Synthetic Example^(b) 77 were carried out insubstantially the same manners except that 4-cyanobenzyl bromide wasused instead of 3-(trifluoromethyl)benzyl bromide to give the titlecompound as a pale yellow oil (28.5 mg, yield 89%).

Reference Synthetic Example^(b) 83 tert-Butylrac-(3R,4R)-4-methyl-3-(4-oxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)piperidin-1-carboxylate

rac-1-[(3R,4R)-4-Methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(20 mg, 0.049 mmol) obtained in Reference Synthetic Example^(b) 36 in1,4-dioxane (2 mL) was stirred with di-tert-butyl bicarbonate (40 mg,0.18 mmol) and 1 M aqueous sodium hydroxide (200 μL. 0.200 mmol) at roomtemperature for 1 hour. After addition of water, the reaction mixturewas extracted with ethyl acetate, and the organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/methanol=1/0→10/1 (v/v)) to give the title compound as acolorless oil (21.1 mg, yield 85%).

Reference Synthetic Example^(b) 84rac-1-[(3R,4R)-1-(4-Fluorophenethyl)-4-methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

rac-1-[(3R,4R)-4-Methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(20 mg, 0.049 mmol) obtained in Reference Synthetic Example^(b) 36 in amixture of N,N-dimethylformamide (2 mL) and dichloromethane (1 mL) wasstirred with 4-fluorophenethyl bromide (22 μL, 0.16 mmol) andN,N-diisopropylethylamine (20 μL, 0.11 mmol) at 50° C. for 2 hours andthen with sodium hydride (60 wt % dispersion in liquid paraffin, 10 mg,0.24 mmol) at 70° C. for 5 hours. The reaction mixture was allowed tocool to room temperature and, after addition of saturated aqueous sodiumchloride, extracted with ethyl acetate, and the organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(hexane/ethyl acetate=1/1→0/1 (v/v)) to give a mixture (4.4 mg)containing the title compound. The mixture was used for the next stepwithout further purification.

Reference Synthetic Example^(b) 85rac-1-[(3R,4R)-1-cyclopentyl-4-methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

rac-1-[(3R,4R)-4-Methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(32 mg, 0.078 mmol) obtained in Reference Synthetic Example^(b) 36 in amixture of methanol (2 mL) and acetic acid (0.2 mL) was stirred withcyclopentanone (100 μL, 1.13 mmol) and 2-picoline borane (50 mg, 0.47mmol) at room temperature for 1 hour. After addition of water, thereaction mixture was extracted with ethyl acetate, and the organic layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure. The resulting colorless oil (38 mg) containing the titlecompound was used for the next step without further purification.

Reference Synthetic Example^(b) 861-{1-[4-(tert-Butyl)cyclohexanecarbonyl]-4-methylpiperidin-3-yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

rac-1-[(3R,4R)-4-Methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(20 mg, 0.049 mmol) obtained in Reference Synthetic Example^(b) 36 inchloroform (2 mL) was stirred with 4-(tert-butyl)cyclohexanecarboxylicacid (20 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodidimidehydrochloride (20 mg, 0.10 mmol) and N,N-diisopropylethylamine (50 μL,0.29 mmol) at room temperature for 2 hours. After addition of 0.1 Maqueous sodium hydroxide, the reaction mixture was extracted with ethylacetate, and the organic layer was washed with 0.1 M hydrochloric acid,dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate) to give two isomers of the title compound in a lesspolar fraction (Reference Synthetic Example^(b) 86a: colorless oil, 9.0mg, yield 32%) and in more polar fraction (Reference SyntheticExample^(b) 86 b: colorless oil, 9.3 mg, yield 33%).

Reference Synthetic Example^(b) 874-Chloro-1{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid

4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(486 mg, 1.56 mmol) obtained in Reference Synthetic Example^(b) 55 inacetic acid (10 mL) was mixed with sulfamic acid (227 mg, 2.34 mmol) and2-methyl-2-butene (486 μL, 4.58 mmol), and then sodium chlorite (254 mg,2.81 mmol) in water (0.5 mL) was added dropwise. The resulting reactionmixture was stirred at room temperature for 2 hours, and after additionof water, adjusted to pH 7 with 1 M aqueous sodium hydroxide andextracted with chloroform. The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethylacetate/methanol=10/1→1/1 (v/v)) to give the title compound as acolorless solid (484 mg, yield 95%).

Reference Synthetic Example^(b) 884-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid (480 mg, 1.47 mmol) in thionyl chloride (3 mL) was stirred at roomtemperature for 2 hours. After addition of toluene, the reaction mixturewas concentrated under reduced pressure, and after addition of toluene,concentrated under reduced pressure. The residue was dissolved indichloromethane (5 mL), and ammonia-methanol solution (7.0 M, 1.0 mL,7.0 mmol) was added dropwise, and the resulting reaction mixture wasstirred for 1 hour. After addition of saturated aqueous sodium chloride,the reaction mixture was extracted with ethyl acetate, and the organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure to give the title compound as a colorless solid (461mg, yield 96%).

Reference Synthetic Example^(b) 894-[(1-Benzylpiperidin-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide(456 mg, 1.40 mmol) was stirred with 1-benzyl-4-aminopiperidine (900 mg,4.73 mmol) and N,N-diisopropylethylamine (250 μL, 1.44 mmol) at 140° C.for 3 hours. The reaction mixture was allowed to cool to roomtemperature and, after addition of water, extracted with ethyl acetate,and the organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (chloroform→ethyl acetate/methanol=1/0→5/1(v/v)) to give the title compound as a colorless solid (542 mg, yield81%).

Reference Synthetic Example^(b) 901-(1-Benzylpiperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione

4-[(1-Benzylpiperidin-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide(484 mg, 1.01 mmol) in N,N-dimethylacetamide (5 mL) was stirred with1,1′-carbonyldiimidazole (486 mg, 3.00 mmol) at 120° C. for 3 hours. Thereaction mixture was allowed to cool to room temperature and, afteraddition of saturated aqueous sodium chloride, extracted with ethylacetate, and the organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (chloroform/methanol=20/1 (v/v)) togive the title compound as a colorless solid (360 mg, yield 70%).

Reference Synthetic Example^(b) 911-(Piperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dionehydrochloride

1-(1-Benzylpiperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione(360 mg, 0.712 mmol) and 5% palladium-carbon (100 mg) in a mixture ofmethanol and 10 wt % hydrogen chloride-methanol solution (0.5 mL) werestirred with at room temperature for 2 hours under a hydrogenatmosphere, then at 40° C. for 5 hours and at room temperature for oneday. The reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure to give the title compound as acolorless solid (324 mg, quantitative yield).

Reference Synthetic Example^(b) 924-{[4-(2,4-Dioxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl)piperidin-1-yl]methyl}benzonitrile

1-(Piperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dionehydrochloride (50 mg, 0.111 mmol) and 4-cyanobenzaldehyde (29 mg, 0.22mmol) in a mixture of methanol (2 ml) and acetic acid (0.2 mL) werestirred with 2-picoline borane (50 mg, 0.47 mmol) at room temperaturefor 2 days. After addition of 1 M aqueous sodium hydroxide, the reactionmixture was extracted with a mixture of ethyl acetate and 2-propanol,and the organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (chloroform/methanol=10/1 (v/v)) to give thetitle compound as a colorless solid (23.4 mg, yield 40%).

Reference Synthetic Example^(b) 931-{1-[(5-Chlorothiophen-2-yl)methyl]piperidin-4-yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione

The reactions in Reference Synthetic Example^(b) 92 were carried out insubstantially the same manners except that5-chlorothiophene-2-carbaldehyde was used instead of 4-cyanobenzaldehydeto give the title compound as a colorless solid (21.1 mg, yield 58%).

Reference Synthetic Example^(b) 941-{1-[4-(Trifluoromethyl)benzyl]piperidin-4-yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione

The reactions in Reference Synthetic Example^(b) 92 were carried out insubstantially the same manners except that4-(trifluoromethyl)benzaldehyde was used instead of 4-cyanobenzaldehydeto give the title compound as a colorless amorphous (28.1 mg, yield44%).

Reference Synthetic Example^(b) 951-Cyclohexyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione

4-(Cyclohexylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide(26 mg, 0.067 mmol) obtained in Reference Synthetic Example^(b) 30 inN,N-dimethylacetamide (1 mL) was stirred with 1,1′-carbonyldiimidazole(22 mg, 0.14 mmol) at 170° C. for 2 hours under microwave irradiation.The reaction mixture was allowed to cool to room temperature and, afteraddition of water, extracted with ethyl acetate, and the organic layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate=1/1 (v/v)) to give the title compound as acolorless solid (13.7 mg, yield 49%).

Reference Synthetic Example^(b) 961-(4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone

Methylmagnesium bromide-diethyl ether solution (3.0 M, 10 mL, 30 mmol)was added dropwise to4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(4.89 g, 15.7 mmol) obtained in Reference Synthetic Example^(b) 55 intetrahydrofuran (50 mL) under cooling with ice, and the reaction mixturewas stirred for 2 hours. After dropwise addition of water and additionof saturated aqueous ammonium chloride, the reaction mixture wasextracted with ethyl acetate, and the organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was dissolved in 1,2-dimethoxyethane (25 mL) and vigorouslystirred with manganese dioxide (9.0 g, 0.10 mol) at 80° C. for 4 hours.The reaction mixture was filtered, and the filtrate was concentratedunder reduced pressure. The residue was dissolved in 1,2-dimethoxyethane(25 mL) and vigorously stirred with manganese dioxide (9.0 g, 0.10 mol)at 80° C. for 4 hours. The reaction mixture was filtered, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate=10/1(v/v)) to give the title compound as an orange oil (3.09 g, yield 61%).(alternative to Reference Synthetic Example^(b) 33)

Reference Synthetic Example^(b) 971-(4-[(1-Benzylpiperidin-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone

1-(4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone(400 mg, 1.23 mmol) and 1-benzylpiperidin-4-amine (1.70 mL, 8.93 mmol)was stirred with N,N-diisopropylethylamine (251 μL. 1.47 mmol) at 140°C. for one day. The reaction mixture was purified by silica gel columnchromatography (hexane/ethyl acetate=1/1 (v/v)) to give the titlecompound (343 mg, yield 58%).

Reference Synthetic Example^(b) 981-(1-Benzylpiperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

1-{4-[(1-Benzylpiperidin-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl}ethanone(343 mg, 0.720 mmol) in N,N-dimethylformamide dimethyl acetal (2 mL) wasstirred at 170° C. for 6 hours under microwave irradiation. The reactionmixture was allowed to cool to room temperature and concentrated underreduced pressure, and the residue was dissolved in tetrahydrofuran (5mL) and stirred with 1 M hydrochloric acid (3 mL) at 80° C. for 1 hour.After addition of saturated aqueous sodium hydrogen carbonate, thereaction mixture was extracted with chloroform, and the organic layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(chloroform/methanol=9/1 (v/v)) to give the title compound (299 mg,yield 85%).

Reference Synthetic Example^(b) 991-(Piperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

1-(1-Benzylpiperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(341 mg, 0.697 mmol) in methanol was stirred with 5% palladium-carbon(500 mg) for one day under a hydrogen atmosphere. The reaction mixturewas filtered, and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography (Hi Flashcolumn amino type manufactured by Yamazen Corporation:chloroform/methanol=9/1/(v/v)) to give the title compound (189 mg, yield68%).

Reference Synthetic Example^(b) 1001-{1-[(5-Chlorothiophen-2-yl)methyl]piperidin-4-yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

1-(Piperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(20 mg, 0.050 mmol) in methanol was stirred with5-chlorothiophen-2-carbaldehyde (6.3 μL, 0.06 mmol), 2-picoline borane(6.4 mg, 0.06 mmol) and acetic acid (100 μL) for one day. The reactionmixture was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (chloroform/methanol=10/1(v/v)) to give the title compound as a colorless oil (20 mg, yield 75%).

Reference Synthetic Example^(b) 1011-{1-[4-(Trifluoromethyl)benzyl]piperidin-4-yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

1-(Piperidin-4-yl)-7-[{2-(trimethylsilyl)ethoxy}methyl]-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(20 mg, 0.050 mmol) obtained in Reference Synthetic Example^(b) 99 indichloromethane was stirred with 4-(trifluoromethyl)benzyl bromide (14.3mg, 0.0600 mmol) and triethylamine (10.5 μL, 0.0750 mmol) for one day.After addition of water, the reaction mixture was extracted withchloroform, and the organic layer as dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (chloroform/methanol=9/1(v/v)) to give the title compound (20 mg, yield 72%).

Reference Synthetic Example^(b) 1024-{[4-(4-Oxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)piperidin-1-yl)methyl}benzonitrile

The reactions in Reference Synthetic Example^(b) 101 were carried out insubstantially the same manners except that 4-cyanobenzyl bromide wasused instead of 4-(trifluoromethyl)benzyl bromide to give the titlecompound (29.7 mg, yield 77%).

Reference Synthetic Example^(b) 1033-Fluoro-4-{[4-(4-oxo-7-{[-2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)piperidin-1-yl]methyl}benzonitrile

The reactions in Reference Synthetic Example^(b) 101 were carried out insubstantially the same manners except that4-(bromomethyl)-3-fluorobenzonitrile was used instead of4-(trifluoromethyl)benzyl bromide to give the title compound as a yellowoil (17.6 mg, yield 66%).

Reference Synthetic Example^(b) 1044-[(1-Benzylpiperidin-4-yl)amino]-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (600 mg, 3.32 mmol)obtained in Reference Synthetic Example^(b) 7 and1-benzylpiperidin-4-amine (2.53 g, 13.3 mmol) in ethylene glycol (300μL) were stirred at 180° C. for 2 hours under microwave irradiation. Thereaction mixture was allowed to cool to room temperature and, afteraddition of water, extracted with chloroform, and the organic layer wasdried over anhydrous magnesium sulfate and concentrated under reducedpressure. The resulting residue was dissolved in 1,4-dioxane (5 mL) andstirred with 4 M hydrogen chloride—1,4-dioxane solution (5 mL) and water(2 mL) at room temperature for one day. The reaction mixture wasconcentrated under reduced pressure, adjusted to pH 9 or above with 1Maqueous sodium hydroxide and extracted with chloroform and water, andthe organic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (Hi Flash column amino type manufactured byYamazen Corporation: hexane/ethyl acetate=1/1 (v/v)) to give the titlecompound (672 mg, yield 60%).

Reference Synthetic Example^(b) 1054-[(1-Benzylpiperidin-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

4-[(1-Benzylpiperidin-4-yl)amino]-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(672 mg, 2.01 mmol) in N,N-dimethylformamide (5 mL) was mixed withsodium hydride (55 wt % dispersion in mineral oil, 436 mg, 10.0 mmol)under cooling with ice, and the reaction mixture was stirred for 30minutes. The reaction mixture was stirred with[2-(chloromethoxyl)ethyl]trimethylsilane (885 μL, 5.00 mmol) at roomtemperature for one day. After addition of water, the reaction mixturewas extracted with chloroform, and the organic layer was dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=1/1 (v/v)) to give the title compound (392 mg, yield 42%).

Reference Synthetic Example^(b) 106{4-[(1-Benzylpiperidin-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl}methanol

4-[(1-Benzylpiperidin-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(289 mg, 0.620 mmol) in methanol was stirred with sodium borohydride(35.3 mg, 0.93 mmol) at room temperature for 1 hour. The reactionmixture was concentrated under reduced pressure and, after addition ofwater, extracted with ethyl acetate. The organic layer was dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=1/1(v/v)) to give the title compound (258 mg, yield 89%).

Reference Synthetic Example^(b) 1075-(Aminomethyl)-N-(1-benzylpiperidin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine

{4-[(1-Benzylpiperidin-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl}methanol(212 mg, 0.454 mmol), phthalimide (134 mg, 0.909 mmol) andtriphenylphosphine (238 mg, 0.909 mmol) in tetrahydrofuran was stirredat room temperature for 30 minutes and with diisopropyl azodicarboxylate(184 mg, 0.909 mmol) for one day. The reaction mixture was concentratedunder reduced pressure and, after addition of water, extracted withethyl acetate. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=1/1/(v/v)) to removetriphenylphosphine oxide. The residue was dissolved in ethanol (10 mL)and stirred with hydrazine monohydrate (1.00 mL, 11.6 mmol) at 80° C.for 1 hour. The reaction mixture was concentrated under reduced pressureand, after addition of water, extracted with chloroform, and the organiclayer was dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=1/1 (v/v)) to give the titlecompound (51.1 mg, yield 24%).

Reference Synthetic Example^(b) 1081-(1-Benzylpiperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-3,4-dihydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one

5-(Aminomethyl)-N-(1-benzylpiperidin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine(38 mg, 0.081 mmol) in dichloromethane was stirred with1,1′-carbonyldiimidazole (20.0 mg, 0.123 mmol) at 80° C. for 1 hour. Thereaction mixture was concentrated under reduced pressure and, afteraddition of water, extracted with ethyl acetate, and the organic layerwas dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (chloroform/methanol=10/1 (v/v)) to give the titlecompound (30.9 mg, yield 77%).

Reference Synthetic Example^(b) 1091-(Piperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-3,4-dihydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one

1-(1-Benzylpiperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-3,4-dihydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one(61 mg, 0.12 mmol) in ethanol was stirred with 5% palladium-carbon (60mg) for one day under a hydrogen atmosphere. The reaction mixture wasfiltered, and the filtrate was concentrated under reduced pressure togive the title compound (48 mg, yield 100%).

Reference Synthetic Example^(b) 1101-[1-(Benzylsulfonyl)piperidin-4-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-3,4-dihydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one

1-(Piperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-3,4-dihydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one(18.5 mg, 0.0460 mmol) in dichloromethane was mixed withphenylmethanesulfonyl chloride (17.5 mg, 0.092 mmol) and triethylamine(12.8 μL, 0.0920 mmol) for 1 hour under cooling with ice. After additionof water, the reaction mixture was extracted with chloroform, and theorganic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (chloroform/methanol=9/1 (v/v)) to give thetitle compound as a pale yellow solid (18.4 mg, yield 72%).

Reference Synthetic Example^(b) 1111-[1-(Pyridin-3-ylmethyl)piperidin-4-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-3,4-dihydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one

The reactions in Reference Synthetic Example^(b) 110 were carried out insubstantially the same manners except that 3-picolyl bromide was usedinstead of phenylmethanesulfonyl chloride to give the title compound (14mg, yield 46%).

Reference Synthetic Example^(b) 1124-{[4-(2-Oxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl)piperidin-1-yl]methyl}benzonitrile

The reactions in Reference Synthetic Example^(b) 110 were carried out insubstantially the same manners except that 4-cyanobenzyl bromide wasused instead of phenylmethanesulfonyl chloride to give the titlecompound (20.6 mg, yield 54%).

Reference Synthetic Example^(b) 1131-{1-[4-(Trifluoromethyl)benzyl]piperidin-4-yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-3,4-dihydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one

The reactions in Reference Synthetic Example^(b) 110 were carried out insubstantially the same manners except that 4-(trifluoromethyl)benzylbromide was used instead of phenylmethanesulfonyl chloride to give thetitle compound (18.9 mg, yield 46%).

Reference Synthetic Example^(b) 1144-(2-Oxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl)-N-(1,3,4-thiadiazol-2-yl)piperidine-1-carboxamide

1-(Piperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-3,4-dihydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one(16.3 mg, 0.0407 mmol) obtained in Reference Synthetic Example^(b) 109and phenyl 1,3,4-thiadiazol-2-ylcarbamate (10.8 mg, 0.0488 mol) obtainedin Reference Synthetic Example^(b) 72 in tetrahydrofuran was stirredwith triethylamine (8.1 μL, 0.061 mmol) at 60° C. for 2 hours. Afteraddition of water, the reaction mixture was extracted with ethylacetate, and the organic layer was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (chloroform/methanol=9/1(v/v)) to give the title compound as a colorless solid (20 mg, yield93%).

Reference Synthetic Example^(b) 1151-[1-(3,3,3-Trifluoropropanoyl)piperidin-4-yl]-7-{[-2-(trimethylsilyl)ethoxy]methyl}-3,4-dihydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one

1-(Piperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-3,4-dihydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one(25 mg, 0.062 mmol) obtained in Reference Synthetic Example^(b) 109 inN,N-dimethylformamide was stirred with 3,3,3-trifluoropropionic acid(8.7 mg, 0.068 mmol),0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (28.1 mg, 0.0740 mmol) and N,N-diisopropylethylamine(21.2 μL, 0.124 mmol) at room temperature for 2 hours. After addition ofwater, the reaction mixture was extracted with ethyl acetate, and theorganic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (chloroform/methanol=10/1 (v/v)) to give thetitle compound as a yellow oil (15.5 mg, yield 49%).

Reference Synthetic Example^(b) 1161-[1-(Thiazol-5-ylmethyl)piperidin-4-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-3,4-dihydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one

1-(Piperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-3,4-dihydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one(20 mg, 0.050 mmol) obtained in Reference Synthetic Example^(b) 109 inmethanol was stirred with thiazol-5-carbaldehyde (6.6 μL, 0.075 mmol),2-picoline borane (8.0 mg, 0.075 mmol) and acetic acid (100 μL) for oneday. The reaction mixture was concentrated under reduced pressure, andthe residue was purified by silica gel column chromatography(chloroform/methanol=10/1 (v/v)) to give the title compound (12 mg,yield 48%).

Reference Synthetic Example^(b) 117rac-4-{[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

The reactions in Reference Synthetic Example^(b) 104 were carried out insubstantially the same manners except thatrac-(3R,4R)-1-benzyl-4-methylpiperidin-3-amine obtained in ReferenceSynthetic Example^(b) 3 was used instead of 1-benzylpiperidin-4-amine togive the title compound as a brown oil (282 mg, yield 30%). (alternativeto Reference Synthetic Example^(b) 38)

Reference Synthetic Example^(b) 118rac-4-{[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

The reactions in Reference Synthetic Example^(b) 105 were carried out insubstantially the same manners except thatrac-4-{[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehydewas used instead of4-[(1-benzylpiperidin-4-yl)amino]-1H-pyrrolo[2,3-b]pyridine-5-carbaldehydeto give the title compound (231 mg, yield 60%). (alternative toReference Synthetic Example^(b) 39)

Reference Synthetic Example^(b) 119rac-(4-{[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol

The reactions in Reference Synthetic Example^(b) 106 were carried out insubstantially the same manners except thatrac-4-{[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehydewas used instead of4-[(1-benzylpiperidin-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehydeto give the title compound as a yellow oil (105 mg, yield 84%).(alternative to Reference Synthetic Example^(b) 40)

Reference Synthetic Example^(b) 120rac-5-(Aminomethyl)-N-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine

The reactions in Reference Synthetic Example^(b) 107 were carried out insubstantially the same manners except thatrac-(4-{[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)methanolwas used instead of{4-[(1-benzylpiperidin-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl}methanolto give the title compound (20.8 mg, yield 21%).

Reference Synthetic Example^(b) 121rac-1-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-3,4-dihydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one

The reactions in Reference Synthetic Example^(b) 108 were carried out insubstantially the same manners except thatrac-5-(aminomethyl)-N-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-4-aminewas used instead of5-(aminomethyl)-N-(1-benzylpiperidin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-4-amineto give the title compound (22 mg, yield 100%).

Reference Synthetic Example^(b) 122 (trans-4-Aminocyclohexyl)methanol

trans-4-Aminocyclohexanecarboxylic acid (314 mg, 2.19 mmol) wasgradually added to sodium bis(2-methoxyethoxy)aluminum hydride-toluenesolution (65 wt %, 3.0 mL) in toluene (3 mL) at 75° C., and the reactionmixture was stirred for 7 hours. The reaction mixture was allowed tocool to room temperature and stirred with 1 M aqueous sodium hydroxide(20 mL) at 80° C. for 10 minutes. The reaction mixture was allowed tocool to room temperature and partitioned between water and toluene, andthe aqueous layer was extracted with chloroform three times. The organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure to give the title compound as a colorless solid (170mg, yield 60%).

Reference Synthetic Example^(b) 1231-(4-{[trans-4-(Hydroxymethyl)cyclohexyl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone

(trans-4-Aminocyclohexyl)methanol (170 mg, 1.32 mmol) and1-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone(120 mg, 0.369 mmol) obtained in Reference Synthetic Example^(b) 96 inN,N-dimethylacetamide (1 mL) were stirred with N,N-diisopropylethylamine(128 μL, 0.735 mmol) at 140° C. for 7 hours. The reaction mixture wasallowed to cool to room temperature and, after addition of saturatedaqueous sodium chloride, extracted with ethyl acetate, and the organiclayer was washed with saturated aqueous sodium chloride, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethyl acetate)to give the title compound as a pale yellow oil (118 mg, yield 77%).

Reference Synthetic Example^(b) 1241-[trans-4-(Hydroxymethyl)cyclohexyl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

The reactions in Reference Synthetic Example^(b) 98 were carried out insubstantially the same manners except that1-(4-{[trans-4-(Hydroxymethyl)cyclohexyl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanonewas used instead of1-{4-[(1-benzylpiperidin-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl}ethanoneto give the title compound as a pale yellow solid (35 mg, yield 29%).

Reference Synthetic Example^(b) 125tert-Butyl(trans-4-methoxycyclohexyl)carbamate

tert-Butyl(trans-4-hydroxycyclohexyl)carbamate (1.0 g, 4.6 mmol) intetrahydrofuran (20 mL) was stirred with sodium hydride (55 wt %dispersion in mineral oil, 24 mg, 6.4 mmol) and 15-crown-5 ether (965μL) for 30 minutes under cooling with ice and then with iodomethane (289μL) at room temperature for 1 hour. Methanol (2 mL) was added to thereaction mixture, and the precipitated solid was removed by filtration.The filtrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate=8/1(v/v)) to give the title compound (708 mg, yield 67%).

Reference Synthetic Example^(b) 126 trans-4-Methoxycyclohexanaminehydrochloride

tert-Butyl(trans-4-methoxycyclohexyl)carbamate in ethanol (5 mL) wasstirred with acetyl chloride (1.5 mL) for one day under cooling withice, and the solvent was concentrated under reduced pressure to give thetitle compound (475 mg, yield 95%).

Reference Synthetic Example^(b) 1271-(4-[(trans-4-Methoxycyclohexyl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone

1-(4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone(228 mg, 0.170 mmol) obtained in Reference Synthetic Example^(a) 96 inethylene glycol (1 mL) was stirred with trans-4-methoxycyclohexanaminehydrochloride and N,N-diisopropylethylamine at 180° C. for 1 hour undermicrowave irradiation. After addition of saturated aqueous sodiumhydrogen carbonate, the reaction mixture was extracted with ethylacetate, and the organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=1/9 (v/v)) togive the title compound as a yellow oil (179 mg, yield 61%).

Reference Synthetic Example^(b) 1281-(trans-4-Methoxycyclohexyl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

1-(4-[(trans-4-Methoxycyclohexyl)amino]-1-{[-2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone(179 mg, 0.428 mmol) in N,N-dimethylformamide dimethyl acetal (3 mL) wasstirred at 170° C. for 6 hours under microwave irradiation. The reactionmixture was allowed to cool to room temperature and concentrated underreduced pressure, and the resulting residue was dissolved intetrahydrofuran (3 mL) and stirred with 1 M hydrochloric acid (3 mL) at80° C. for 1 hour. The reaction mixture was allowed to cool to roomtemperature and, after addition of saturated aqueous sodium hydrogencarbonate, extracted with chloroform, and the organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(chloroform/methanol=9/1 (v/v)) to give the title compound (141 mg,yield 77%).

Reference Synthetic Examples^(b) 129 To 134

The reactions in Reference Synthetic Example^(b) 101 were carried out insubstantially the same manners except that2-(bromomethyl)-5-(trifluoromethyl)furan, 2-(bromomethyl)-5-nitrofuran,ethyl 5-(chloromethyl)furan-2-carboxylate,4-(chloromethyl)-1,2-difluorobenzene,1,2-dichloro-4-(chloromethyl)benzene or5-(chloromethyl)-2-(trifluoromethyl)pyridine was used instead of4-(trifluoromethyl)benzyl bromide to give the compounds of ReferenceExamples^(b) 129 to 134. The names, morphologies and yields of thecompounds synthesized are shown in Table^(b) 5.

TABLE^(b) 5 Rf Compound Name Yield 1291-(1-{[5-(trifluoromethyl)furan-2-yl]methyl}piperidin- 74%4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)- one 1301-{1-[(5-nitrofuran-2-yl)methyl]piperidin-4-yl}- 84%7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3,h][1,6]naphthyridin-4(7H)-one 131 Ethyl 74%5-{[4-(4-oxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)piperidin-1-yl]methyl}furan-2-carboxylate 1321-[1-(3,4-difluorobenzyl)piperidin-4-yl]-7-{[2- 82%(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one 1331-[1-(3,4-dichlorobenzyl)piperidin-4-yl]-7-{[2- 95%(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one 1341-(1-{[6-(trifluoromethyl)pyridin-3-yl]methyl}piperidin- 79%4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)- one

Reference Synthetic Example^(b) 135 To 143

The reactions in Reference Synthetic Example^(b) 100 were carried out insubstantially the same manners except that2-chlorothiazole-5-carbaldehyde,4-fluoro-3-(trifluoromethyl)benzaldehyde,5-nitrothiophene-3-carbaldehyde, 5-bromofuran-2-carbaldehyde,5-bromothiophene-2-carbaldehyde, 4-bromothiophene-2-carbaldehyde,2-bromothiazole-5-carbaldehyde,2,2-difluorobenzo[d][1,3]dioxole-5-carbaldehyde or1H-indole-5-carbaldehyde was used instead of5-chlorothiophene-2-carbaldehyde to give the compounds of ReferenceExamples^(b) 135 to 143. The names, morphologies and yields of thecompounds synthesized are shown in Table^(b) 6.

TABLE^(b) 6 Rf Compound Name Yield 1351-{1-[(2-chlorothiazol-5-yl)methyl]piperidin-4- 82%yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one 1361-{1-[4-fluoro-3-(trifluoromethyl)benzyl]piperidin- 86%4-yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one 1371-{1-[(5-nitrothiophen-3-yl)methyl]piperidin-4- 86%yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one 1381-{1-[(5-bromofuran-2-yl)methyl]piperidin-4-yl}- 80%7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one 1391-{1-[(5-bromothiophen-2-yl)methyl]piperidin-4- 78%yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one 1401-{1-[(4-bromothiophen-2-yl)methyl]piperidin-4- 65%yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one 1411-{1-[(2-bromothiazol-5-yl)methyl]piperidin-4- 80%yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one 1421-{1-[(2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl] 94%piperidin-4-yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin- 4(7H)-one 1431-{1-[(1H-indol-5-yl)methyl]piperidin-4-yl}-7- 81%{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

Reference Synthetic Example^(b) 1441-[1-(5-Chlorothiophene-2-carbonyl)piperidin-4-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

1-(Piperidin-4-yl)-7-{[-2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(20 mg, 0.050 mmol) obtained in Reference Synthetic Example^(b) 99 inN,N-dimethylformamide (2 mL) was stirred with5-chlorothiophene-2-carboxylic acid (13.4 mg, 0.0825 mmol),N,N-diisopropylethylamine (25.5 μL, 0.150 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (34.2 mg, 0.0899 mmol) for one day. After additionof water, the reaction mixture was extracted with ethyl acetate, and theorganic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (chloroform/methanol=9/1 (v/v)) to give thetitle compound (40.0 mg, quantitative yield).

Reference Synthetic Examples^(b) 145 To 150

The reactions in Reference Synthetic Example^(b) 92 were carried out insubstantially the same manners except thattert-butyl(2-oxoethyl)carbamate, 5-bromothiophene-2-carbaldehyde,2-(tetrahydro-2H-thiopyran-4-yl)acetaldehyde, cyclopropanecarbaldehyde,2-methylbutanal or 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde was usedinstead of 4-cyanobenzaldehyde to give the compounds of ReferenceSynthetic Examples^(b) 145 to 150. The names, morphologies and yields ofthe compounds synthesized are shown in Table^(b) 7.

TABLE^(b) 7 Rf Compound Name Morphology Yield 145 tert-butyl Colorless89% {2-[4-(2,4-dioxo-7-{[2-(trimethylsilyl)ethoxy]methyl}- solid2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl)piperidin- 1-yl]ethyl}carbamate 1461-{1-[(5-bromothiophen-2-yl)methyl]piperidin- Colorless 70%4-yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}- solid1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine- 2,4(3H,7H)-dione 1471-{1-[2-(tetrahydro-2H-thiopyran-4-yl)ethyl]piperidin- Yellow 36%4-yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}- oil1H-pyrrolo[3′,2′:5,6]pyrido[4, 3-d]pyrimidine-2,4(3H,7H)-dione 1481-[1-(cyclopropylmethyl)piperidin-4-yl]-7- Colorless 51%{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3′, solid2′:5,6]pyrido[4,3-d]pyrimidine-2, 4(3H,7H)-dione 1491-[1-(2-mothylbutyl)piperidin-4-yl]-7-{[2- Colorless 56%(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3′, solid2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H, 7H)-dione 1501-{1-[2-(tetrahydro-2H-pyran-4-yl)ethyl]piperidin- Colorless 80%4-yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}- solid1H-pyrrolo[3′,2′:5,6]pyrido[4, 3-d]pyrimidine-2,4(3H,7H)-dione

Reference Synthetic Example^(b) 1512-[4-(2,4-Dioxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl)piperidin-1-yl]acetonitrile

1-(Piperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dionehydrochloride (40.0 mg, 0.0885 mmol) obtained in Reference SyntheticExample^(b) 91 in acetonitrile (1 mL) was mixed with2-chloroacetonitrile (8.2 μL, 0.133 mmol) and N,N-diisopropylethylamine(31.0 μL, 0.177 mmol) and stirred at 60° C. for 26 hours. The reactionmixture was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography(chloroform→methanol/chloroform=8/92 (v/v)) to give the title compoundas a colorless solid (31.2 mg, yield 78%).

Reference Synthetic Examples^(b) 152 To 156

The reactions in Reference Synthetic Example^(b) 151 were carried out insubstantially the same manners except that 2,2,2-trifluoroethyltrifluoromethanesulfonate, 5-bromopentanenitrile,6-bromo-1,1,1-trifluorohexane, 4-bromobutanenitrile or2-(bromomethyl)tetrahydrofuran was used instead of 2-chloroacetonitrileto give the compounds of Reference Synthetic Examples^(b) 152 to 156.The names, morphologies and yields of the compounds synthesized areshown in Table^(b) 8.

TABLE^(b) 8 Rf Compound Name Morphology Yield 1521-[1-(2,2,2-trifluoroethyl)piperidin- Colorless 81%4-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}- solid1H-pyrrolo[3′,2′:5,6]pyrido[4, 3-d]pyrimidine-2,4(3H,7H)-dione 1535-[4-(2,4-dioxo-7-{[2-(trimethylsilyl)ethoxy]methyl}- Colorless 78%2,3,4,7-tetrahydro- solid 1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl)piperidin-1-yl]pentanenitrile 1541-[1-(6,6,6-trifluorohexyl)piperidin- Pale yellow 83%4-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}- solid1H-pyrrolo[3′,2′:5,6]pyrido[4, 3-d]pyrimidine-2,4(3H,7H)-dione 1554-[4-(2,4-dioxo-7-{[2-(trimethylsilyl)ethoxy]methyl}- Colorless 76%2,3,4,7-tetrahydro- solid 1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl)piperidin-1-yl]butanenitrile 1561-{1-[(tetrahydrofuran-2-yl)methyl]piperidin- Pale orange 65%4-yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}- solid 1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H, 7H)-dione

Reference Synthetic Example^(b) 1573-[4-(2,4-Dioxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl)piperidin-1-yl]propanenitrile

1-(Piperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dionehydrochloride (40.0 mg, 0.0885 mmol) obtained in Reference SyntheticExample^(b) 91 in ethanol (1 mL) was refluxed with acrylonitrile (11.5μL, 0.176 mmol) and N,N-diisopropylethylamine (18.9 μL, 0.110 mmol) for8.5 hours. The reaction mixture was concentrated under reduced pressure,and the residue was purified by silica gel column chromatography(chloroform→methanol/chloroform=6/94 (v/v)) to give the title compoundas a colorless solid (27.3 mg, yield 66%).

Reference Synthetic Example^(b) 158 4-Aminoadamantan-1-ol

Concentrated sulfuric acid (35 mL) was mixed with concentrated nitricacid (4.5 mL) and 2-adamantylamine (5.10 g, 4.57 mmol) under coolingwith ice, and the reaction mixture was stirred at room temperature for 2hours. The reaction mixture was added to ice water and adjusted to pH 10with 7.5 M aqueous sodium hydroxide. After addition of water, thereaction mixture was extracted with chloroform, and the organic layerwas dried over anhydrous magnesium sulfate and concentrated underreduced pressure to give the title compound as a yellow solid (2.79 g,yield 61%).

Reference Synthetic Example^(b) 159 159a:Benzyl[(1R,2s,3S,5s,7s)-5-hydroxyadamantan-2-yl]carbamate 159b:Benzyl[(1R,2r,3S,5s,7s)-5-hydroxyadamantan-2-yl]carbamate

4-Aminoadamantan-1-ol (2.57 g, 15.4 mmol) in tetrahydrofuran (25 mL) wasmixed with benzyl chloroformate (2.30 mL, 16.1 mmol) and 1 M aqueoussodium hydroxide (16.0 mL, 16.0 mmol) under cooling with ice and thenstirred at room temperature for one day. After addition of 10% aqueouspotassium hydrogen sulfate, the reaction mixture was extracted withethyl acetate, and the organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=1/2 (v/v)) to givebenzyl[(1R,2s,3S,5s,7s)-5-hydroxyadamantan-2-yl]carbamate (ReferenceSynthetic Example^(b) 159a; yellow oil, 1.72 g, yield 37%) in a morepolar fraction andbenzyl[(1R,2r,3S,5s,7s)-5-hydroxyadamantan-2-yl]carbamate (ReferenceSynthetic Example^(b) 159 b; yellow oil, 2.24 g, yield 48%) in a lesspolar fraction.

Reference Synthetic Example^(b) 160(1s,3R,4s,5S,7s)-4-Aminoadamantan-1-ol

Benzyl[(1R,2s,3S,5s,7s)-5-hydroxyadamantan-2-yl]carbamate (318 mg, 1.05mmol) obtained in Reference Synthetic Example^(b) 159a and 5%palladium-carbon (63 mg) in methanol (2 mL) were stirred at roomtemperature for one day under a hydrogen atmosphere. The reactionmixture was filtered, and the filtrate was concentrated under reducedpressure to give the title compound as a colorless solid (144 mg, yield82%).

Reference Synthetic Example^(b) 161(1s,3R,4r,5S,7s)-4-Aminoadamantan-1-ol

Benzyl[(1R,2r,3S,5s,7s)-5-hydroxyadamantan-2-yl]carbamate (2.24 g, 7.46mmol) obtained in Reference Synthetic Example^(b) 159 b and 5%palladium-carbon (700 mg) in methanol (30 mL) were stirred at roomtemperature for one day under a hydrogen atmosphere. The reactionmixture was filtered, and the filtrate was concentrated under reducedpressure to give the title compound as a colorless solid (1.29 g,quantitative yield).

Reference Synthetic Example^(b) 162 tert-Butyl3-oxoazetidine-1-carboxylate

tert-Butyl 3-hydroxyazetidine-1-carboxylate (4.02 g, 23.2 mmol) indichloromethane (305 mL) was mixed with Dess-Martin Periodinane (9.55 g,22.5 mmol) under cooling with ice and then stirred at room temperaturefor 3 hours. After addition of 10% aqueous sodium thiosulfate andsaturated aqueous sodium hydrogen carbonate under cooling with ice, thereaction mixture was extracted with chloroform, and the organic layerwas washed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (hexane/ethylacetate=2/1 (v/v)) to give the title compound as a colorless solid (3.39g, yield 85%).

Reference Synthetic Example^(b) 163 tert-Butyl3-(cyanomethylene)azetidine-1-carboxylate

Diethyl cyanomethylphosphonate (3.54 g, 20.0 mmom) in tetrahydrofuran(20 mL) was added to potassium tert-butoxide (2.03 g, 21.1 mmol) intetrahydrofuran (30 mL) under cooling with ice and stirred for 30minutes. The reaction mixture was mixed with tert-butyl3-oxoazetidine-1-carboxylate (2.96 g, 17.3 mmol) in tetrahydrofuran (15mL) and stirred at room temperature for 1 day, and after addition ofwater, extracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography (hexane/ethylacetate=3/1 (v/v)) to give the title compound as a colorless solid (1.93g, yield 58%).

Reference Synthetic Example^(b) 164 tert-Butyl3-(cyanomethyl)azetidine-1-carboxylate

tert-Butyl 3-(cyanomethylene)azetidine-1-carboxylate (823 mg, 4.24 mmol)in a mixture of methanol (20 mL) and 1,4-dioxane (10 mL) was stirredwith 5% palladium-carbon (129 mg) for one day under a hydrogenatmosphere. The reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) togive the title compound as a colorless oil (657 mg, yield 79%).

Reference Synthetic Example^(b) 165 2-(Azetidin-3-yl)acetonitrilehydrochloride

tert-Butyl 3-(cyanomethyl)azetidine-1-carboxylate (621 mg, 3.17 mmol) in1,4-dioxane (4 mL) was stirred with 4 M hydrogen chloride-1,4-dioxanesolution (6 mL) at room temperature for 1 day. The reaction mixture wasconcentrated under reduced pressure to give the title compound as acolorless oil (543 mg, quantitative yield).

Reference Synthetic Example^(b) 1664-{[trans-4-(Hydroxymethyl)cyclohexyl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide(680 mg, 2.09 mmol) obtained in Reference Synthetic Example^(b) 88 inN,N-dimethylacetamide (1.1 mL) was mixed with N,N-diisopropylethylamine(1.1 mL) and (trans-4-Aminocyclohexyl)methanol (945 mg, 7.31 mmol)obtained in Reference Synthetic Example^(b) 122 and stirred at 130° C.for 3 hours. The reaction mixture was allowed to cool to roomtemperature and, after addition of saturated aqueous ammonium chloride,extracted with ethyl acetate, and the organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane=5/1 (v/v)) to give the title compound as a colorlesssolid (781 mg, yield 89%).

Reference Synthetic Example^(b) 1671-[trans-4-(Hydroxymethyl)cyclohexyl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione

4-{[trans-4-(Hydroxymethyl)cyclohexyl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide(270 mg, 0.645 mmol) in N,N-dimethylacetamide (3 mL) was mixed withN,N-diisopropylethylamine (3 mL) and 1,1′-carbonyldiimidazole (1.04 g,6.45 mmol) and stirred at 120° C. for 3 hours. The reaction mixture wasallowed to cool to room temperature and stirred with 1M aqueous sodiumhydroxide (3 mL) and acetonitrile (3 mL) for 5 hours. After addition ofwater, the reaction mixture was extracted with ethyl acetate, and theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane=9/1 (v/v)) to give the titlecompound as a colorless solid (206 mg, yield 73%).

Reference Synthetic Example^(b) 168trans-4-(2,4-Dioxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexanecarbaldehyde

1-[trans-4-(Hydroxymethyl)cyclohexyl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione(107 mg, 0.240 mmol) in a mixture of toluene (1 mL) and dimethylsulfoxide (0.25 mL) was mixed with 2-iodoxybenzoic acid (80.9 mg, 0.288mmol) and stirred at 50° C. for 2 hours. After addition of saturatedaqueous sodium thiosulfate and saturated aqueous sodium hydrogencarbonate, the reaction mixture was stirred at room temperature for 30minutes, and extracted with ethyl acetate, and the organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane=1/1→7/3 (v/v)) to give the title compound as acolorless solid (70.1 mg, yield 66%).

Reference Synthetic Example^(b) 1691-(4-{[(2,2,2-Trifluoroethyl)amino]methyl}cyclohexyl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione

trans-4-(2,4-Dioxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexanecarbaldehyde(30.4 mg, 0.0680 mmol) in a mixture of methanol (0.5 mL) and acetic acid(50 μL) was stirred with 2,2,2-trifluoroethanamine hydrochloride (12.1mg, 0.089 mmol) and 2-picoline borane (9.50 mg, 0.089 mmol) at roomtemperature for 1 day. After addition of 1 M aqueous sodium hydroxide,the reaction mixture was extracted with ethyl acetate, and the organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by silica gel thin layerchromatography (ethyl acetate/hexane=1/1 (v/v)) to give the titlecompound as a colorless solid (32.3 mg, yield 90%).

Reference Synthetic Example^(b) 1703-[trans-4-(2,4-Dioxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexyl]acrylonitrile

trans-4-(2,4-Dioxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexanecarbaldehyde(34.2 mg, 0.0770 mmol) obtained in Reference Synthetic Example^(b) 168in tetrahydrofuran (2 mL) was mixed with diethyl cyanomethylphosphonate(37 μL, 0.235 mmol) and sodium hydride (55 wt % dispersion in mineraloil, 10 mg, 0.235 mmol) under cooling with ice and then stirred at roomtemperature for 30 minutes. After addition of water, the reactionmixture was extracted with ethyl acetate, and the organic layer waswashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethylacetate/hexane=1/2→1/0 (v/v)) to give the title compound as a colorlesssolid (32.0 mg, yield 92%).

Reference Synthetic Examples^(b) 171 And 172

The reactions in Reference Synthetic Example^(b) 89 were carried out insubstantially the same manners except that(1s,3R,4r,5S,7s)-4-aminoadamantan-1-ol obtained in Reference SyntheticExample^(b) 161 or (1s,3R,4s,5S,7s)-4-aminoadamantan-1-ol obtained inReference Synthetic Example^(b) 160 was used instead of1-benzyl-4-aminopiperidine to give the compounds of ReferenceExamples^(b) 171 and 172. The names, morphologies and yields of thecompounds synthesized are shown in Table^(b) 9.

TABLE^(b) 9 Rf Compound Name Morphology Yield 1714-{[(1R,2r,3S,5s,7s)-5-hydroxyadamantan- Brown 86%2-yl]amino}-1-{[2-(trimethylsilyl)- oilethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine- 5-carboxamide 1724-{[(1R,2s,3S,5s,7s)-5-hydroxyadamantan- Colorless 58%2-yl]amino}-1-{[2-(trimethylsilyl)- oilethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine- 5-carboxamide

Reference Synthetic Examples^(b) 173 And 174

The reactions in Reference Synthetic Example^(b) 90 were carried out insubstantially the same manners except that4-{[(1R,2r,3S,5s,7s)-5-hydroxyadamantan-2-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamideobtained in Reference Synthetic Example^(b) 171 or4-{[(1R,2s,3S,5s,7s)-5-hydroxyadamantan-2-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamideobtained in Reference Synthetic Example^(b) 172 was used instead of4-[(1-benzylpiperidin-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamideto give the compounds of Reference Synthetic Examples^(b) 173 and 174.The names, morphologies and yields of the compounds synthesized areshown in Table^(b) 10.

TABLE^(b) 10 Rf Compound Name Morphology Yield 1731-[(1R,2r,3S,5s,7s)-5-hydroxyadamantan- Colorless 95%2-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}- solid1H-pyrrolo[3′,2′:5,6]pyrido[4, 3-d]pyrimidine-2,4(3H,7H)-dione 1741-[(1R,2s,3S,5s,7s)-5-hydroxyadamantan- Yellow 99%2-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}- oil1H-pyrrolo[3′,2′:5,6]pyrido[4, 3-d]pyrimidine-2,4(3H,7H)-dione

Reference Synthetic Examples^(b) 175 And 176

The reactions in Reference Synthetic Example^(b) 97 were carried out insubstantially the same manners except that(1s,3R,4r,5S,7s)-4-aminoadamantan-1-ol obtained in Reference SyntheticExample^(b) 161 or (1s,3R,4s,5S,7s)-4-aminoadamantan-1-ol obtained inReference Synthetic Example^(b) 160 was used instead of1-benzylpiperidine-4-amine to give the compounds of Reference SyntheticExamples^(b) 175 and 176. The names, morphologies and yields of thecompounds synthesized are shown in Table^(b) 11.

TABLE^(b) 11 Rf Compound Name Morphology Yield 1751-(4-{[(1R,2r,3S,5s,7s)-5-hydroxy- Yellow 78%adamantan-2-yl]amino}-1-{[2- solid (trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2, 3-b]pyridin-5-yl)ethanone 1761-(4-{[(1R,2s,3S,5s,7s)-5-hydroxy- Yellow 91%adamantan-2-yl]amino}-1-{[2- solid (trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2, 3-b]pyridin-5-yl)ethanone

Reference Synthetic Examples^(b) 177 And 178

The reactions in Reference Synthetic Example^(b) 98 were carried out insubstantially the same manners except that1-(4-{[(1R,2r,3S,5s,7s)-5-hydroxyadamantan-2-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanoneobtained in Reference Synthetic Example^(b) 175 or1-(4-{[(1R,2s,3S,5s,7s)-5-hydroxyadamantan-2-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanoneobtained in Reference Synthetic Example^(b) 176 was used instead of1-{4-[(1-benzylpiperidin-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl}ethanoneto give the compounds of Reference Synthetic Examples^(b) 177 and 178.The names, morphologies and yields of the compounds synthesized areshown in Table^(b) 12.

TABLE^(b) 12 Rf Compound Name Morphology Yield 1771-[(1R,2r,3S,5s,7s)-5-hydroxyadamantan- Yellow 82%2-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}- solid1H-pyrrolo[2,3-h][1,6]naphthyridin- 4(7H)-one 1781-[(1R,2s,3S,5s,7s)-5-hydroxyadamantan- Yellow 83%2-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}- solid1H-pyrrolo[2,3-h][1,6]naphthyridin- 4(7H)-one

Reference Synthetic Example^(b) 1793-Amino-1,1,1-trifluoro-2-(pyridin-3-yl)propan-2-ol

Isopropylmagnesium chloride-lithium chloride complex-tetrahydrofuransolution (1.3 M, 20.7 mL, 27.0 mmol) was added dropwise to5-bromo-2-chloropyridine (5.20 g, 27.0 mmol) in tetrahydrofuran (40 mL)under cooling with ice, and the reaction mixture was stirred for 30minutes and then mixed with ethyl 2,2,2-trifluoroacetate (11.5 g, 81.0mmol) under cooling with ice and stirred at room temperature for 10minutes. After addition of 1M hydrochloric acid, the reaction mixturewas extracted with ethyl acetate, and the organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure to givea yellow oil. The yellow oil was dissolved in nitromethane (30 mL) andstirred with potassium carbonate (3.73 g, 27.0 mmol) at room temperaturefor 30 minutes. The reaction mixture was added to 1M hydrochloric acidand extracted with ethyl acetate, and the organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=3/1 (v/v)) to give a yellow oil. The yellow oil was dissolved intetrahydrofuran (20 mL), mixed with 10% palladium-carbon (600 mg) andtriethylamine (2.60 mL, 18.7 mmol) and then stirred at room temperaturefor one day under a hydrogen atmosphere. The reaction mixture wasfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate→ethyl acetate/methanol/triethylamine=9/1/1 (v/v/v)) to give thetitle compound as a colorless solid (913 mg, yield 31%(4 steps)).

Synthetic Example^(b) 11-Cyclohexyl-4-methyl-1,2,4,7-tetrahydropyrrolo[3′,2′:5,6]pyrido[4,3-d][1,3]oxazine

Crude1-cyclohexyl-4-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-1,2,4,7-tetrahydropyrrolo[3′,2′:5,6]pyrido[4,3-d][1,3]oxazine(9 mg) obtained in Reference Synthetic Example^(b) 23 inN,N-dimethylformamide (1 mL) was stirred with ethylenediamine (50 μL,0.75 mmol) and tetrabutylammonium fluoride (1.0 M tetrahydrofuransolution, 100 μL, 0.100 mmol) at 80° C. for 1 hour and allowed to coolto room temperature. After addition of saturated aqueous sodiumchloride, the reaction mixture was extracted with ethyl acetate, and theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel thinlayer chromatography (hexane/ethyl acetate=1/2 (v/v)) to give the titlecompound as a colorless amorphous (1.8 mg, yield 29% (two steps)).

Synthetic Example^(b) 21-Cyclohexyl-1,2,4,7-tetrahydropyrrolo[3′,2′:5,6]pyrido[4,3-d][1,3]oxazine

1-Cyclohexyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-1,2,4,7-tetrahydropyrrolo[3′,2′:5,6]pyrido[4,3-d][1,3]oxazine(17 mg, 0.044 mmol) obtained in Reference Synthetic Example^(b) 11 inN,N-dimethylformamide (1 mL) was stirred with ethylenediamine (50 μL,0.75 mmol) and tetrabutylammonium fluoride (1.0 M tetrahydrofuransolution, 120 μL, 0.120 mmol) at 80° C. for 2 hours and allowed to coolto room temperature. After addition of saturated aqueous sodiumchloride, the reaction mixture was extracted with ethyl acetate, and theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel thinlayer chromatography (ethyl acetate/methanol=20/1 (v/v)) to give thetitle compound as a colorless solid (2.0 mg, yield 18%).

Synthetic Example^(b) 31-Cyclohexyl-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

1-Cyclohexyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(9 mg, 0.02 mmol) obtained in Reference Synthetic Example^(b) 24 inN,N-dimethylformamide (1 mL) was stirred with ethylenediamine (25 μL,0.37 mmol) and tetrabutylammonium fluoride (1.0 M tetrahydrofuransolution, 70 μL, 0.070 mmol) at 80° C. for 30 minutes and allowed tocool to room temperature. After addition of saturated aqueous sodiumchloride, the reaction mixture was extracted with ethyl acetate, and theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel thinlayer chromatography (ethyl acetate/methanol=20/1 (v/v)) to give thetitle compound as a colorless solid (3.3 mg, yield 54%).

Synthetic Example^(b) 4rac-1-[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

rac-1-[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(90 mg, 0.18 mmol) obtained in Reference Synthetic Example^(b) 35 inN,N-dimethylformamide (3 mL) was stirred with ethylenediamine (50 μL,0.75 mmol) and tetrabutylammonium fluoride (1.0 M tetrahydrofuransolution, 900 μL, 0.900 mmol) at 80° C. for 2 hours and allowed to coolto room temperature. After addition of water, the reaction mixture wasextracted with chloroform, and the organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was mixed with ethyl acetate, and the solid was collected byfiltration to give the title compound as a pale orange solid (46.5 mg,yield 70%).

Synthetic Example^(b) 5rac-1-[(3R,4R)-4-Methylpiperidin-3-yl]-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-onehydrochloride

rac-1-[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(16 mg, 0.043 mmol) and 5% palladium-carbon (15 mg) in methanol (2 mL)was stirred with hydrogen chloride-methanol solution (10 wt %, 20 μL) at40° C. for 2 hours under a hydrogen atmosphere. The reaction mixture wasfiltered, and the filtrate was concentrated under reduced pressure togive the title compound as a pale yellow solid (15 mg, quantitativeyield).

Synthetic Example^(b) 6rac-1-[(3R,4R)-1-(2,3-Difluorobenzyl)-4-methylpiperidin-3-yl]-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(Synthetic Example^(b) 6a)rac-1-[(3R,4R)-1,4-Dimethylpiperidin-3-yl]-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(Synthetic Example^(b) 6b)

rac-1-[(3R,4R)-4-methylpiperidin-3-yl]-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-onehydrochloride (18 mg, 0.057 mmol) and 2,3-difluorobenzaldehyde (10 mg,0.070 mmol) in a mixture of methanol (1 mL)/acetic acid (1 mL) wasstirred with 2-picoline borane (10 mg, 0.094 mmol) at room temperaturefor one day. After addition of saturated aqueous sodium hydrogencarbonate and 1 M aqueous sodium hydroxide, the reaction mixture wasextracted with chloroform, and the organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel thin layer chromatography(chloroform/methanol=20/1 (v/v)) to giverac-1-[(3R,4R)-1-(2,3-difluorobenzyl)-4-methylpiperidin-3-yl]-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(less polar fraction: 6.1 mg, yield 26%) as a pale yellow solid andrac-1-[(3R,4R)-1,4-dimethylpiperidin-3-yl]-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(more polar fraction: 5.9 mg, yield 35%) as a colorless oil.

Synthetic Example^(b) 7rac-3-[(3R,4R)-4-Methyl-3-(4-oxo-4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)piperidin-1y1]-3-oxopropanenitrile

rac-1-[(3R,4R)-4-Methylpiperidin-3-yl]-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-onehydrochloride (15 mg, 0.040 mmol) obtained in Synthetic Example^(b) 5,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10 mg,0.052 mmol), N-hydroxybenzotriazole (6 mg, 0.04 mmol), 2-cyanoaceticacid (5 mg, 0.06 mmol) and N,N-diisopropylethylamine (30 μL, 0.017 mmol)in N,N-dimethylformamide (0.5 mL) was stirred at room temperature for 2hours. After addition of water, the reaction mixture was extracted withchloroform, and the aqueous layer was extracted with a mixture ofchloroform/2-propanol. The organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel thin layer chromatography (ethylacetate/methanol=20/1 (v/v)), and the crude product was further purifiedby silica gel thin layer chromatography (NH-PLC05 plate manufactured byFuji Silysia Chemical Ltd.: chloroform/methanol=10/1 (v/v)) to give thetitle compound as a colorless solid (2.5 mg, yield 17%).

Synthetic Example^(b) 8rac-1-[(3R,4R)-1-(2-Cyclopropylacetyl)-4-methylpiperidin-3-yl]-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

rac-1-[(3R,4R)-4-Methylpiperidin-3-yl]-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-onehydrochloride (20 mg, 0.054 mmol) obtained in Synthetic Example^(b) 5,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20 mg, 0.10mmol), 2-cyclopropylacetic acid (10 μL) and N,N-diisopropylethylamine(26 μL, 0.015 mmol) in N,N-dimethylformamide (1 mL) was stirred at roomtemperature for 6 hours. After addition of saturated aqueous sodiumhydrogen carbonate, the reaction mixture was extracted with chloroform,and the organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel thin layer chromatography (chloroform/methanol=15/1 (v/v)), and thecrude product was further purified by silica gel thin layerchromatography (NH-PLC05 plate manufactured by Fuji Silysia ChemicalLtd.: chloroform/methanol=30/1 (v/v)) to give the title compound as acolorless solid (7.9 mg, yield 40%).

Synthetic Example^(b) 9rac-1-[(3R,4R)-4-Methyl-1-(3,3,3-trifluoropropanoyl)piperidin-3-yl]-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

rac-1-[(3R,4R)-4-Methylpiperidin-3-yl]-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-onehydrochloride (15.6 mg, 0.0489 mmol) obtained in Synthetic Example^(b)5, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.5 mg,0.0978 mmol), 3,3,3-trifluoropropionic acid (13 μL, 0.098 mmol) andN,N-diisopropylethylamine (26 μL, 0.015 mmol) in N,N-dimethylformamide(1 mL) was stirred at room temperature for one day. After addition ofsaturated aqueous sodium hydrogen carbonate, the reaction mixture wasextracted with ethyl acetate, and the organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel thin layer chromatography(chloroform/methanol=4/1 (v/v)) to give the title compound as acolorless solid (12.2 mg, yield 64%).

Synthetic Example^(b) 10rac-1-[(3R,4R)-1-(Isobutylsulfonyl)-4-methylpiperidin-3-yl]-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

rac-1-[(3R,4R)-1-(Isobutylsulfonyl)-4-methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(18 mg, 0.034 mmol) obtained in Reference Synthetic Example^(b) 37 indichloromethane (1 mL) was stirred with trifluoroacetic acid (1 mL) atroom temperature for 3 hours. After addition of saturated aqueous sodiumhydrogen carbonate, the reaction mixture was extracted with chloroform,and the organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was dissolved in amixture of dichloromethane (1 mL) and methanol (1 mL) and stirred withethylenediamine (100 μL, 1.50 mmol) and 1 M aqueous sodium hydroxide(100 μL, 0.100 mmol) at room temperature for one day. After addition ofwater, the reaction mixture was extracted with chloroform, and theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel thinlayer chromatography (ethyl acetate/methanol=20/1 (v/v)) to give thetitle compound as a colorless solid (8.2 mg, yield 60%).

Synthetic Example^(b) 11rac-1-[(3R,4R)-4-Methyl-1-(2,2,2-trifluoroethylsulfonyl)piperidin-3-yl]-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

rac-1-[(3R,4R)-4-Methylpiperidin-3-yl]-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-onehydrochloride (16 mg, 0.050 mmol) obtained in Synthetic Example^(b) 5 ina mixture of dichloromethane (1 mL) and N,N-dimethylformamide (100 μL)was mixed with N,N-diisopropylethylamine (30 μL, 0.17 mmol) and2,2,2-trifluoroethanesulfonyl chloride (20 mg, 0.11 mmol) under coolingwith ice and stirred at room temperature for one day. After addition ofsaturated aqueous sodium hydrogen carbonate, the reaction mixture wasextracted with chloroform, and the organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel thin layer chromatography (ethylacetate/methanol=10/1 (v/v)) to give the title compound as a colorlesssolid (2.5 mg, yield 12%).

Synthetic Example^(b) 121-Cyclohexyl-1,4-dihydropyrrolo[3′,2′:5,6]pyrido[3,4-b][1,4]thiazine-4,4(7H)-dione

Crude1-cyclohexyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydropyrrolo[3′,2′:5,6]pyrido[3,4-b][1,4]thiazine-4,4(7H)-dione(8.5 mg) obtained in Reference Synthetic Example^(b) 28 indichloromethane (1 mL) was stirred with trifluoroacetic acid (1 mL) atroom temperature for 3 hours. After addition of saturated aqueous sodiumhydrogen carbonate, the reaction mixture was extracted with chloroform,and the organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The resulting residue was dissolvedin methanol (1 mL) and stirred with ethylenediamine (20 μL, 0.30 mmol)and 1 M aqueous sodium hydroxide (20 μL, 0.020 mmol) at room temperaturefor 3 hours. The precipitated solid was collected by filtration to givethe title compound as a colorless solid (1.7 mg, yield 39% (two steps)).

Synthetic Example^(b) 131-Cyclohexyl-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-4(7H)-one

1-Cyclohexyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-4(7H)-one(9 mg, 0.02 mmol) obtained in Reference Synthetic Example^(b) 32 indichloromethane (2 mL) was stirred with trifluoroacetic acid (1 mL) atroom temperature for 2 hours. After addition of saturated aqueous sodiumhydrogen carbonate, the reaction mixture was extracted with chloroform,and the organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The resulting residue was dissolvedin methanol (2 mL) and dichloromethane (1 mL) and stirred withethylenediamine (50 μL, 0.75 mmol) and 1 M aqueous sodium hydroxide (50μL, 0.050 mmol) at room temperature for 3 days. After addition of water,the reaction mixture was extracted with chloroform, and the organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by silica gel thin layerchromatography (chloroform/methanol=30/1 (v/v)) to give the titlecompound as a colorless solid (2.1 mg, yield 35%).

Synthetic Example^(b) 14rac-1-[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]-1,2,4,7-tetrahydropyrrolo[3′,2′:5,6]pyrido[4,3-d][1,3]oxazine

rac-1-[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1,2,4,7-tetrahydropyrrolo[3′,2′:5,6]pyrido[4,3-d][1,3]oxazine(64.6 mg, 0.131 mmol) obtained in Reference Synthetic Example^(b) 41 indichloromethane (2 mL) was stirred with trifluoroacetic acid (1 mL) atroom temperature for 2 hours, and the reaction mixture was concentratedunder reduced pressure. The resulting residue was stirred withdichloromethane (4 mL), methanol (2 mL), ethylenediamine (200 μL, 3.00mmol) and 1 M aqueous sodium hydroxide (2 mL, 2 mmol) at roomtemperature for 1 hour. The reaction solution was concentrated underreduced pressure, and after addition of water, extracted withchloroform. The organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel thin layer chromatography (chloroform/methanol=10/1 (v/v)) togive the title compound as a pale yellow amorphous (28.2 mg, yield 59%).

Synthetic Example^(b) 15rac-1-[(3R,4R)-4-Methylpiperidin-3-yl]-1,2,4,7-tetrahydropyrrolo[3′,2′:5,6]pyrido[4,3-d][1,3]oxazine

rac-1-[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]-1,2,4,7-tetrahydropyrrolo[3′,2′:5,6]pyrido[4,3-d][1,3]oxazine(28.2 mg, 0.0777 mmol) in ethanol was stirred with 5% palladium-carbon(30 mg) and concentrated hydrochloric acid (2 drops) at 50° C. for 2hours under a hydrogen atmosphere. The reaction mixture was allowed tocool to room temperature and filtered, and the filtrate was concentratedunder reduced pressure to give the title compound (21.2 mg, yield 100%).

Synthetic Example^(b) 16rac-3-[(3R,4R)-4-Methyl-3-(pyrrolo[3′,2′:5,6]pyrido[4,3-d][1,3]oxazin-1(2H,4H,7H)-yl)piperidin-1-yl]-3-oxopropanenitrile

rac-1-[(3R,4R)-4-Methylpiperidin-3-yl]-1,2,4,7-tetrahydropyrrolo[3′,2′:5,6]pyrido[4,3-d][1,3]oxazine(21.2 mg, 0.0777 mmol) in N,N-dimethylformamide was stirred withcyanoacetic acid (15 mg, 0.18 mmol),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (67 mg, 0.18 mmol), N,N-diisopropylethylamine (44.9μL, 0.264 mmol) at room temperature for one day. After addition ofwater, the reaction mixture was extracted with ethyl acetate, and theorganic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (Hi Flash column amino typemanufactured by Yamazen Corporation: chloroform/methanol=20/1 (v/v)) togive the title compound as a yellow oil (3 mg, yield 10%).

Synthetic Example^(b) 171-Cyclohexyl-3,4-dihydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one

1-Cyclohexyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-3,4-dihydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one(46.6 mg, 0.116 mmol) obtained in Reference Synthetic Example^(b) 13 indichloromethane (3 mL) was stirred with trifluoroacetic acid (1 mL) atroom temperature for 2 hours. The reaction mixture was concentratedunder reduced pressure, and the resulting residue was stirred withdichloromethane (2 mL), methanol (1 mL), ethylenediamine (200 μL, 3.00mmol) and 1 M aqueous sodium hydroxide (1 mL, 1 mmol) for one day. Thereaction mixture was concentrated under reduced pressure, and afteraddition of water, extracted with chloroform, and the organic layer wasdried over anhydrous magnesium sulfate and concentrated under reducedpressure to give the title compound as a colorless solid (22.2 mg, yield70%).

Synthetic Example^(b) 181-Cyclohexyl-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one1-Cyclohexyl-3,4-dihydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one

(18 mg, 0.066 mmol) in chloroform (2 mL) was stirred with manganesedioxide (100 mg, 1.15 mmol) at 50° C. for 5 hours. The reaction mixturewas filtered, and the filtrate was purified by silica gel columnchromatography (Hi Flash column amino type manufactured by YamazenCorporation: chloroform/methanol=10/1 (v/v)) to give the title compoundas a colorless solid (0.58 mg, yield 3.2%).

Synthetic Example^(b) 191-Cyclohexyl-1,4-dihydro-7H-pyrrolo[3′,2′:5,6]pyrido[3,4-e]pyrimidine

1-Cyclohexyl-1,4-dihydro-7-{[2-(trimethylsilyl)ethoxy]methyl}-pyrrolo[3′,2′:5,6]pyrido[3,4-e]pyrimidine(48.8 mg, 0.127 mmol) obtained in Reference Synthetic Example^(b) 14 indichloromethane (2 mL) was stirred with trifluoroacetic acid (1 mL) forone day. The reaction mixture was concentrated under reduced pressureand stirred with dichloromethane (2 mL), methanol (1 mL),ethylenediamine (300 μL, 4.49 mmol) and 1 M aqueous sodium hydroxide (1mL, 1 mmol) for one day. The reaction mixture was concentrated underreduced pressure and extracted with chloroform, and the organic layerwas dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (Hi Flash column amino type manufactured by YamazenCorporation: chloroform/methanol=10/1 (v/v)) to give the title compoundas a colorless solid (11 mg, yield 34%).

Synthetic Example^(b) 209-Cyclohexyl-3H-imidazo[4,5-h][1,6]naphthyridin-6(9H)-one

9-Cyclohexyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-h][1,6]naphthyridin-6(9H)-one(57.5 mg, 0.144 mmol) obtained in Reference Synthetic Example^(b) 48 indichloromethane (2 mL) was stirred with trifluoroacetic acid (2 mL) atroom temperature for 1 hour. The reaction mixture was concentrated underreduced pressure, and the resulting residue was stirred withdichloromethane (4 mL), methanol (1 mL), ethylenediamine (200 μL, 3.00mmol) and 1 M aqueous sodium hydroxide (1 mL, 1 mmol) at roomtemperature for 2 hours. The reaction mixture was concentrated underreduced pressure, and the resulting residue was purified by silica gelchromatography (chloroform/methanol=10/1 (v/v)) to give the titlecompound as a pale yellow solid (23.0 mg, yield 59%).

Synthetic Examples^(b) 21 to 47

The reactions in Synthetic Example^(b) 10 were carried out insubstantially the same manners except that the compounds obtained inReference Synthetic Examples^(b) 51, 54, 59 to 71, 73 or 75 to 85 wereused instead ofrac-1-[(3R,4R)-1-(isobutylsulfonyl)-4-methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-oneto give the compounds of Synthetic Examples^(b) 21 to 47. The names,morphologies and yields of the compounds synthesized are shown inTables^(b) 13 to 15.

TABLE^(b) 13 Ex Compound Name Morphology Yield 21rac-1-[(3R,4R)-1-benzyl-4-methylpiperidin colorless oil 34%3-yl]-9-bromo-1H-pyrrolo[2, 3-h][1,6]naphthyridin-4(7H)-one 22rac-1-[(3R,4R)-1-benzyl-4-methylpiperidin- colorless oil 69%3-yl]-9-chloro-1H-pyrrolo[2, 3-h][1,6]naphthyridin-4(7H)-one 23rac-1-[(3R,4R)-1-benzyl-4-methylpiperidin- colorless oil 60%3-yl]-3-methyl-1H-pyrrolo[2, 3-h][1,6]naphthyridin-4(7H)-one 24rac-1-[(3R,4R)-1-benzyl-4-methylpiperidin- colorless oil 2.3% 3-yl]-3-bromo-1H-pyrrolo[2, (two steps) 3-h][1,6]naphthyridin-4(7H)-one25 rac-2-{[(3R,4R)-4-methyl-3-(4-oxo- colorless 44%4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin- solid1-yl)piperidin-1-yl]sulfonyl}benzonitrile 26rac-3-{[(3R,4R)-4-methyl-3-(4-oxo- colorless 52%4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin- solid1-yl)piperidin-1-yl]sulfonyl}benzonitrile 27 rac-(3R,4R)-ethyl colorless53% 4-methyl-3-(4-oxo-4,7-dihydro-1H-pyrrolo[2, solid3-h][1,6]naphthyridin-1-yl)piperidine- 1-carboxylate 28rac-(3R,4R)-4-methyl-3-(4-oxo-4,7- colorless 75%dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin- solid1-yl)-N-[2-(trifluoromethyl)phenyl]piperidine- 1-carboxamide 29rac-(3R,4R)-4-methyl-3-(4-oxo-4,7- colorless 36%dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin- solid1-yl)-N-[3-(trifluoromethyl)phenyl]piperidine- 1-carboxamide 30rac-1-{(3R,4R)-4-methyl-1-[2-(trifluoromethyl)benzoyl]piperidin-colorless 37% 3-yl}- solid 1H-pyrrolo[2,3-h][1,6]naphthyridin- 4(7H)-one31 rac-1-{(3R,4R)-4-methyl-1-[3-(trifluoromethyl)benzoyl]piperidin-colorless 66% 3-yl}- solid 1H-pyrrolo[2,3-h][1,6]naphthyridin- 4(7H)-one32 rac-1-{(3R,4R)-1-[2-(4-fluorophenyl)acetyl]- colorless 79%4-methylpiperidin-3-yl}- solid 1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one 33rac-1-((3R,4R)-4-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}piperidin-colorless 57% 3-yl)-1H-pyrrolo[2,3-h][1,6]naphthyridin- solid 4(7H)-one

TABLE^(b) 14 Ex Compound Name Morphology Yield 34rac-1-{(3R,4R)-4-methyl-1-[4-(trifluoromethyl)benzoyl]piperidin-colorless 70% 3-yl}- solid 1H-pyrrolo[2,3-h][1,6]naphthyridin- 4(7H)-one35 rac-(3R,4R)-benzyl colorless oil 56%4-methyl-3-(4-oxo-4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)piperidine- 1-carboxylate 36rac-(3R,4R)-4-methyl-3-(4-oxo-4,7- pale yellow 81%dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin- solid1-yl)-N-(1,3,4-thiadiazol- 2-yl)piperidine-1-carboxamide 37rac-(3R,4R)-4-methyl-N-(3-methylisothiazol- pale yellow 90%5-yl)-3-(4-oxo-4,7-dihydro- solid 1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)piperidine-1-carboxamide 38rac-1-[(3R,4R)-1-(cyclopentanecarbonyl)- pale yellow 76%4-methylpiperidin-3-yl]-1H-pyrrolo[2, solid 3-h][1,6]naphthyridin-4(7H)-one 39 rac-1-{(3R,4R)-4-methyl-1-[3-(trifluoromethyl)benzyl]piperidin-pale yellow 42% 3-yl}- solid 1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one 40rac-1-{(3R,4R)-4-methyl-1-[4-(trifluoromethyl)benzyl]piperidin- yellowsolid 85% 3-yl}- 1H-pyrrolo[2,3-h][1,6]naphthyridin- 4(7H)-one 41rac-1-{(3R,4R)-4-methyl-1-[2-(trifluoromethyl)benzyl]piperidin- yellowsolid 57% 3-yl}- (two steps) 1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one 42 rac-3-{[(3R,4R)-4-methyl-3-(4-oxo- pale yellow 88%4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin- solid1-yl)piperidin-1-yl]methyl}benzonitrile 43rac-2-{[(3R,4R)-4-methyl-3-(4-oxo- pale yellow 88%4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin- solid1-yl)piperidin-1-yl]methyl}benzonitrile 44rac-4-{[(3R,4R)-4-methyl-3-(4-oxo- yellow solid 41%4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)piperidin-1-yl]methyl}benzonitrile 45 rac-(3R,4R)-tert-butylcolorless 53% 4-methyl-3-(4-oxo-4,7-dihydro-1H-pyrrolo[2, solid3-h][1,6]naphthyridin-1-yl)piperidine- 1-carboxylate

TABLE^(b) 15 Ex Compound Name Morphology Yield 46rac-1-[(3R,4R)-1-(4-fluorophenethyl)- colorless oil 12%4-methylpiperidin-3-yl]-1H-pyrrolo[2, (two steps)3-h][1,6]naphthyridin-4(7H)- one 47rac-1-[(3R,4R)-1-cyclopentyl-4-methyl- colorless 55%piperidin-3-yl]-1H-pyrrolo[2,3- solid (two steps)h][1,6]naphthyrdin-4(7H)-one

Synthetic Example^(b) 481-{1-[4-(tert-Butyl)cyclohexanecarbonyl]-4-methylpiperidin-3-yl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

The reactions in Synthetic Example^(b) 10 were carried out insubstantially the same manners except that Reference SyntheticExamples^(b) 86a or 86b obtained in Reference Synthetic Example^(b) 86were used instead ofrac-1-[(3R,4R)-1-(isobutylsulfonyl)-4-methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-oneto give the two isomers of the title compound, Synthetic Example^(b) 48a(colorless amorphous, 5.0 mg, 71%) or Synthetic Example^(b) 48 b(colorless amorphous, 4.1 mg, yield 56%).

Synthetic Examples^(b) 49 to 53

The reactions in Synthetic Example^(b) 10 were carried out insubstantially the same manners except that the compounds obtained inReference Synthetic Examples^(b) 90 and 92 to 95 were used instead ofrac-1-[(3R,4R)-1-(isobutylsulfonyl)-4-methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-oneto give the compounds of Synthetic Examples^(b) 49 to 53. The names,morphologies and yields of the compounds synthesized are shown inTable^(b) 16.

TABLE^(b) 16 Ex Compound Name Morphology Yield 491-(1-benzylpiperidin-4-yl)-1H-pyrrolo[3′, colorless 40%2′:5,6]pyrido[4,3-d]pyrimidine- solid 2,4(3H,7H)-dione 504-{[4-(2,4-dioxo-2,3,4,7-tetrahydro- colorless 69%1H-pyrrolo[3′,2′:5,6]pyrido[4, solid3-d]pyrimidin-1-yl)piperidin-1-yl]methyl}- benzonitrile 511-{1-[(5-chlorothiophen-2-yl)methyl]piperidin- colorless 59%4-yl}-1H-pyrrolo[3′, solid 2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione 52 1-{1-[4-(trifluoromethyl)benzyl]piperidin-4- colorless80% yl}-1H-pyrrolo[3′,2′:5, solid 6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione 53 1-cyclohexyl-1H-pyrrolo[3′,2′:5,6]pyrido[4, colorless 21%3-d]pyrimidine-2,4(3H,7H)- solid dione

Synthetic Examples^(b) 54 to 58

The reactions in Synthetic Example^(b) 10 were carried out insubstantially the same manners except that the compounds obtained inReference Synthetic Examples^(b) 98 and 100 to 103 were used instead ofrac-1-[(3R,4R)-1-(isobutylsulfonyl)-4-methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-oneto give the compounds of Synthetic Examples^(b) 54 to 58. The names,morphologies and yields of the compounds synthesized are shown inTable^(b) 17.

TABLE^(b) 17 Ex Compound Name Morphology Yield 541-(1-benzylpiperidin-4-yl)-1H-pyrrolo[2, colorless 53%3-h][1,6]naphthyridin-4(7H)- solid one 551-{1-[(5-chlorothiophen-2-yl)methyl]piperidin- pale yellow 95%4-yl}-1H-pyrrolo[2,3- solid h][1,6]naphthyridin-4(7H)-one 561-{1-[4-(trifluoromethyl)benzyl]piperidin- yellow solid 98%4-yl}-1H-pyrrolo[2,3-h][1, 6]naphthyridin-4(7H)-one 574-{[4-(4-oxo-4,7-dihydro-1H-pyrrolo[2, yellow solid 69%3-h][1,6]naphthyridin-1-yl)piperidin- 1-yl]methyl}benzonitrile 583-fluoro-4-{[4-(4-oxo-4,7-dihydro- yellow solid 98%1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)piperidin-1-yl]methyl}benzonitrile

Synthetic Examples^(b) 59 to 67

The reactions in Synthetic Example^(b) 10 were carried out insubstantially the same manners except that the compounds obtained inReference Synthetic Examples^(b) 108 and 110 to 116 and 121 were usedinstead ofrac-1-[(3R,4R)-1-(isobutylsulfonyl)-4-methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-oneto give the compounds of Synthetic Examples^(b) 59 to 67. The names,morphologies and yields of the compounds synthesized are shown inTable^(b) 18.

TABLE^(b) 18 Ex Compound Name Morphology Yield 591-(1-benzylpiperidin-4-yl)-3,4-dihydro- colorless 99%1H-pyrrolo[3′,2′:5,6]pyrido[4, solid 3-d]pyrimidin-2(7H)-one 601-[1-(benzylsulfonyl)piperidin-4- colorless 47%yl]-3,4-dihydro-1H-pyrrolo[3′,2′: solid5,6]pyrido[4,3-d]pyrimidin-2(7H)- one 611-[1-(pyridin-3-ylmethyl)piperidin- colorless 43%4-yl]-3,4-dihydro-1H-pyrrolo[3′, solid2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)- one 624-{[4-(2-oxo-2,3,4,7-tetrahydro-1H- brown solid 72%pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl)piperidin-1-yl]methyl}benzonitrile 631-{1-[4-(trifluoromethyl)benzyl]piperidin- brown solid 77%4-yl}-3,4-dihydro-1H-pyrrolo[3′, 2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one 64 4-(2-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′, brown solid 86%2′:5,6]pyrido[4,3-d]primidin- 1-yl)-N-(1,3,4-thiadiazol-2-yl)piperidine-1-carboxamide 65 1-[1-(3,3,3-trifluoropropanoyl)piperidin-colorless 32% 4-yl]-3,4-dihydro-1H-pyrrolo[3′, solid2′:5,6]pyrido[4,3-d]pyrimidin- 2(7H)-one 661-[1-(thiazol-5-ylmethyl)piperidin- colorless 92%4-yl]-3,4-dihydro-1H-pyrrolo[3′, solid2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)- one 67rac-1-[(3R,4R)-1-benzyl-4-methylpiperidin- brown solid 56%3-yl]-3,4-dihydro-1H-pyrrolo[3′, 2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one

Synthetic Example^(b) 681-(Piperidin-4-yl)-3,4-dihydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one

1-(1-Benzylpiperidin-4-yl)-3,4-dihydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one(25.6 mg, 0.0708 mmol) obtained in Synthetic Example^(b) 59 and 5%palladium-carbon (30 mg) in ethanol was stirred with 10 wt % hydrogenchloride-methanol (2 drops) at 50° C. for 2 hours under a hydrogenatmosphere. The reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure to give the title compound as acolorless solid (9 mg, yield 46%).

Synthetic Examples^(b) 69 to 85

The reactions in Synthetic Example^(b) 10 were carried out insubstantially the same manners except that the compounds obtained inReference Synthetic Examples^(b) 124 and 128 to 144 were used instead ofrac-1-[(3R,4R)-1-(isobutylsulfonyl)-4-methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-oneto give the compounds of Synthetic Examples^(b) 69 to 85. The names,morphologies and yields of the compounds synthesized are shown inTables^(b) 19 and 20.

TABLE^(b) 19 Ex Compound Name Morphology Yield 691-(trans-4-(hydroxymethyl)cyclohexyl)- pale yellow 38%1H-pyrrolo[2,3-h][1,6]naphthyridin- solid 4(7H)-one 701-(trans-4-methoxycyclohexyl)-1H- brown solid 42%pyrrolo[2,3-h][1,6]naphthyridin- 4(7H)-one 711-(1-{[5-(trifluoromethyl)furan- yellow solid quant2-yl]methyl}piperidin-4-yl)-1H-pyrrolo[2, 3-h][1,6]naphthyridin-4(7H)-one 72 1-{1-[(5-nitrofuran-2-yl)methyl]piperidin- Yellow oil 33%4-yl}-1H-pyrrolo[2,3-h][1, 6]naphthyridin-4(7H)-one 73 ethyl yellowquant 5-{[4-(4-oxo-4,7-dihydro-1H-pyrrolo[2, amorphous3-h][1,6]naphthyridin-1-yl)piperidin- 1-yl]methyl}furan-2-carboxylate 741-[1-(3,4-difluorobenzyl)piperidin- Yellow oil 80%4-yl]-1H-pyrrolo[2,3-h][1,6]naphthyridin- 4(7H)-one 751-[1-(3,4-dichlorobenzyl)piperidin- yellow solid quant4-yl]-1H-pyrrolo[2,3-h][1,6]naphthyridin- 4(7H)-one 761-(1-{[6-(trifluoromethyl)pyridin- yellow solid quant3-yl]methyl}piperidin-4-yl)-1H- pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one 77 1-{1-[(2-chlorothiazol-5-yl)methyl]piperidin- Yellow oil69% 4-yl}-1H-pyrrolo[2, 3-h][1,6]naphthyridin-4(7H)-one 781-{1-[4-fluoro-3-(trifluoromethyl)benzyl]- yellow solid 96%piperidin-4-yl}-1H-pyrrolo[2, 3-h][1,6]naphthyridin-4(7H)- one 791-{1-[(5-nitrothiophen-3-yl)methyl]piperidin- brown solid 27%4-yl}-1H-pyrrolo[2, 3-h][1,6]naphthyridin-4(7H)-one 801-{1-[(5-bromofuran-2-yl)methyl]piperidin- yellow solid quant4-yl}-1H-pyrrolo[2,3-h][1, 6]naphthyridin-4(7H)-one 811-{1-[(5-bromothiophen-2-yl)methyl]piperidin- yellow solid quant4-yl}-1H-pyrrolo[2, 3-h][1,6]naphthyridin-4(7H)-one 821-{1-[(4-bromothiophen-2-yl)methyl]piperidin- yellow solid quant4-yl}-1H-pyrrolo[2, 3-h][1,6]naphthyridin-4(7H)-one

TABLE^(b) 20 Ex Compound Name Morphology Yield 831-{1-[(2-bromothiazol-5-yl)methyl]piperidin- yellow solid quant4-yl}-1H-pyrrolo[2,3-h][1, 6]naphthyridin-4(7H)-one 841-{1-[(2,2-difluorobenzo[d][1,3]dioxol- yellow solid quant5-yl)methyl]piperidin-4-yl}- 1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one 85 1-{1-[(1H-indol-5-yl)methyl]piperidin- yellow solid 38%4-yl}-1H-pyrrolo[2,3-h][1,6]naphthyridin- 4(7H)-one

Synthetic Example^(b) 861-{1-[(2-Methylthiazol-4-yl)methyl]piperidin-4-yl}-1H-pyrrolo[2,3-h]{1,6]naphthyridin-4(7H)-one

1-(Piperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one(30 mg, 0.075 mmol) obtained in Reference Synthetic Example^(b) 99 indichloromethane was stirred with 4-(chloromethyl)-2-methylthiazolehydrochloride (13.3 mg, 0.0901 mmol) and triethylamine (16 μL, 0.11mmol) at 40° C. for one day. After addition of water, the reactionmixture was extracted with chloroform, and the organic layer was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was roughly purified by silica gel columnchromatography (chloroform/methanol=9/1 (v/v)), and the resulting crudeproduct was dissolved in dichloromethane (2 mL) and stirred withtrifluoroacetic acid (1 mL) at room temperature for 1 hour. The reactionmixture was concentrated under reduced pressure, and the residue wasdissolved in a mixture of dichloromethane (2 mL) and methanol (1 mL) andstirred with ethylenediamine (200 μL) and 1 M aqueous sodium hydroxide(1 mL) for one day. After addition of water, the reaction mixture wasextracted with chloroform, and the organic layer was dried overanhydrous magnesium sulfate and concentrated under reduced pressure togive the title compound as a brown oil (6.3 mg, yield 22%).

Synthetic Example^(b) 871-[1-(5-Chlorothiophene-2-carbonyl)piperidin-4-yl]-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one

1-[1-(5-Chlorothiophene-2-carbonyl)piperidin-4-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-oneobtained in Reference Synthetic Example^(b) 144 in dichloromethane (2mL) was stirred with trifluoroacetic acid (1 mL) at room temperature for1 hour. The reaction mixture was concentrated under reduced pressure,and the residue was dissolved in a mixture of dichloromethane (2 mL) andmethanol (1 mL) and stirred with ethylenediamine (200 μL) and 1 Maqueous sodium hydroxide (1 mL) for one day. The precipitated solid wascollected by filtration to give the title compound as a colorless solid(22.8 mg, yield 73%).

Synthetic Examples^(b) 88 to 107

The reactions in Synthetic Example^(b) 14 were carried out insubstantially the same manners except that the compounds obtained inReference Synthetic Examples^(b) 145 to 157, 167, 169, 170, 173, 174,177 or 178 were used instead ofrac-1-[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1,2,4,7-tetrahydropyrrolo[3′,2′:5,6]pyrido[4,3-d][1,3]oxazineto give the compounds of Synthetic Examples^(b) 88 to 107. The names,morphologies and yields of the compounds synthesized are shown inTables^(b) 21 and 22.

TABLE^(b) 21 Ex Compound Name Morphology Yield 881-[1-(2-aminoethyl)piperidin-4-yl]- brown solid 90%1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine- 2,4(3H,7H)-dione 891-{1-[(5-bromothiophen-2-yl)methyl]piperidin- Colorless 77%4-yl}-1H-pyrrolo[3′,2′:5′, solid 6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione 90 1-{1-[2-(tetrahydro-2H-thiopyran-4- Colorless 26%yl)ethyl]piperidin-4-yl}-1H-pyrrolo[3′, solid2′:5,6]pyrido[4,3-d]pyrimidine- 2,4(3H,7H)-dione 911-[1-(cyclopropylmethyl)piperidin-4- Colorless 24%yl]-1H-pyrrolo[3′,2′:5,6]pyrido[4, solid 3-d]pyrimidine-2,4(3H,7H)-dione92 1-[1-(2-methylbutyl)piperidin-4-yl]- Colorless 4%1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]- solid pyrimidine-2,4(3H,7H)-dione 931-{1-[2-(tetrahydro-2H-pyran-4-yl)ethyl]- Colorless 13%piperidin-4-yl}-1H-pyrrolo[3′, solid2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H, 7H)-dione 942-[4-(2,4-dioxo-2,3,4,7-tetrahydro- Colorless 3%1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin- solid1-yl)piperidin-1-yl]acetonitrile 951-[1-(2,2,2-trifluoroethyl)piperidin- Colorless 38%4-yl]-1H-pyrrolo[3′,2′:5,6]pyrido[4, solid3-d]pyrimidine-2,4(3H,7H)-dione 96 5-[4-(2,4-dioxo-2,3,4,7-tetrahydro-Colorless 88% 1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin- solid1-yl)piperidin-1-yl]pentanenitrile 971-[1-(6,6,6-trifluorohexyl)piperidin- Colorless 29%4-yl]-1H-pyrrolo[3′,2′:5,6]pyrido[4, solid3-d]pyrimidine-2,4(3H,7H)-dione 98 4-[4-(2,4-dioxo-2,3,4,7-tetrahydro-Colorless 4% 1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin- solid1-yl)piperidin-1-yl]butanenitrile

TABLE^(b) 22 Ex Compound Name Morphology Yield 991-{1-[(tetrahydrofuran-2-yl)methyl]piperidin- Colorless 40%4-yl}-1H-pyrrolo[3′,2′:5,6]pyrido[4, solid3-d]pyrimidine-2,4(3H,7H)-dione 1003-[4-(2,4-dioxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′, Colorless 43%2′:5,6]pyrido[4,3-d]pyrimidin- solid 1-yl)piperidin-1-yl]propanenitrile101 1-[trans-4-(hydroxymethyl)cyclohexyl]-1H- Colorless 74%pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine- solid 2,4(3H,7H)-dione 1021-(trans-4-{[(2,2,2-trifluoroethyl)amino]methyl}cyclohexyl)- Colorless75% 1H-pyrrolo[3′,2′:5, solid 6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione103 3-[trans-4-(2,4-dioxo-2,3,4,7-tetrahydro- Colorless 53%1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin- solid1-yl)cyclohexyl]acrylonitrile 1041-((1R,2r,3S,5s,7s)-5-hydroxyadamantan- Colorless 41%2-yl)-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine- solid2,4(3H,7H)-dione 105 1-((1R,2s,3S,5s,7s)-5-hydroxyadamantan- Brown 25%2-yl)-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine- oil 2,4(3H,7H)-dione106 1-((1R,2r,3S,5s,7s)-5-hydroxyadamantan- Colorless 55%2-yl)-1H-pyrrolo[2,3-h][1,6]naphthyridin- solid 4(7H)-one 1071-((1R,2s,3S,5s,7s)-5-hydroxyadamantan- Colorless 69%2-yl)-1H-pyrrolo[2,3-h][1,6]naphthyridin- solid 4(7H)-one

Synthetic Example^(b) 1081-[1-(2-Morpholinoethyl)piperidin-4-yl]-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione

1-(Piperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dionehydrochloride (30.0 mg, 0.0664 mmol) obtained in Reference SyntheticExample^(b) 91 and 4-(2-chloroethyl)morpholine hydrochloride (36.8 mg,0.198 mmol) in acetonitrile (1.5 mL) were mixed withN,N-diisopropylethylamine (79.5 μL, 0.462 mmol) and stirred at 60° C.for 15 hours and then with 4-(2-chloroethyl)morpholine hydrochloride(36.8 mg, 0.198 mmol) and N,N-diisopropylethylamine (34.1 μL, 0.198mmol) for 30.5 hours. The reaction mixture was allowed to cool to roomtemperature and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography(methanol/chloroform=3/97→12/88 (v/v)). The resulting crude product wasdissolved in dichloromethane (1.5 mL) and stirred with trifluoroaceticacid (0.5 mL) at room temperature for 2 hours. The reaction mixture wasazeotropically distilled with toluene under reduced pressure, and theresidue was dissolved in methanol (2 mL) and stirred withethylenediamine (75 μL, 1.12 mmol) and 1 M aqueous sodium hydroxide (0.8mL) at room temperature for 2.5 hours. The reaction mixture wasconcentrated under reduced pressure and, after addition of water,extracted with 1-butanol four times. The organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography (HiFlash column amino type manufactured by Yamazen Corporation:methanol/chloroform=0/1→9/91 (v/v)) to give the title compound as acolorless solid (1.5 mg, yield 6% (three steps)).

Synthetic Example^(b) 109 tert-Butyl4-({2-[4-(2,4-dioxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl)piperidin-1-yl]ethyl}amino)piperidine-1-carboxylate

1-[1-(2-Aminoethyl)piperidin-4-yl]-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione(20.0 mg, 0.0609 mmol) obtained in Synthetic Example^(b) 88 andtert-butyl 4-oxopiperidine-1-carboxylate (24.3 mg, 0.122 mmol) in amixture of methanol (1 mL) and acetic acid (100 μL) were stirred with2-picoline borane (13.0 mg, 0.122 mmol) at room temperature for 17hours. The reaction mixture was basified with 1 M aqueous sodiumhydroxide and extracted with a mixture of chloroform and 2-propanol fourtimes. The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (methanol/chloroform=0/1→1/0 (v/v)) to givethe title compound as a colorless solid (18.0 mg, yield 57%).

Synthetic Example^(b) 1101-(1-{2-[(Cyclopropylmethyl)amino]ethyl}piperidin-4-yl)-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione

The reactions in Synthetic Example^(b) 109 were carried out insubstantially the same manners except that cyclopropanecarbaldehyde wasused instead of tert-butyl 4-oxopiperidine-1-carboxylate to give thetitle compound as a colorless solid (5.5 mg, yield 23%).

Synthetic Example^(b) 1111-{1-[2-(Piperidin-4-ylamino)ethyl]piperidin-4-yl}-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione

tert-Butyl4-({2-[4-(2,4-dioxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl)piperidin-1-yl]ethyl}amino)piperidine-1-carboxylate(16.9 mg, 0.0330 mmol) obtained in Synthetic Example^(b) 109 in amixture of dichloromethane (1 mL) and methanol (1 mL) was stirred withtrifluoroacetic acid (100 μL, 1.31 mmol) at room temperature for 2.5hours and then with trifluoroacetic acid (400 μL, 5.23 mmol) at roomtemperature for 2.5 hours and then with trifluoroacetic acid (500 μL,6.53 mmol) at room temperature for 4.5 hours and then withtrifluoroacetic acid (2 mL, 26.1 mmol) at room temperature for 16 hours.The reaction mixture was concentrated under reduced pressure, and theresulting residue was purified by silica gel chromatography (Hi Flashcolumn amino type manufactured by Yamazen Corporation: methanol/ethylacetate=1/4→4/1 (v/v)) to give the title compound as a colorless solid(4.21 mg, yield 30%).

Synthetic Example^(b) 1121-{trans-4-[((R)-3-Hydroxypyrrolidin-1-yl)methyl]cyclohexyl}-1H-Pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione

trans-4-(2,4-Dioxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexanecarbaldehyde(30.0 mg, 0.067 mmol) obtained in Reference Synthetic Example^(b) 168 ina mixture of methanol (0.5 mL) and acetic acid (50 μL) was stirred with(R)-3-hydroxy-pyrrolidine (14.3 mg, 0.088 mmol) and 2-picoline borane(9.4 mg, 0.088 mmol) at room temperature for 1 day. After addition of 1Maqueous sodium hydroxide, the reaction mixture was extracted with ethylacetate, and the organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel thin layer chromatography (ethyl acetate/methanol=10/1 (v/v))to give the compound as a colorless solid. The resulting colorless solidwas dissolved in dichloromethane (1.0 mL) and stirred withtrifluoroacetic acid (0.4 mL) at room temperature for 5 hours. Thereaction mixture was concentrated under reduced pressure, and theresulting residue was stirred with methanol (0.7 mL), ethylenediamine(30 μL) and 1 M aqueous sodium hydroxide (30 μL) at room temperature for1 day. The reaction mixture was filtered and the resulting solid waswashed with water and methanol to give the title compound as a colorlesssolid (20.0 mg, yield 52% (three steps)).

Synthetic Examples^(b) 113 to 132

The reactions in Synthetic Example^(b) 112 were carried out insubstantially the same manners except that 3-hydroxyazetidinehydrochloride, thiomorpholine-1,1-dioxide, 4,4-difluoropiperidine,3,3′-iminodipropionitrile, cyclopropylmethylamine,(R)-3-cyanopyrrolidine, 3,3-dimethylazetidine, 2-methylaminoethanol,2-(phenylmethyl)aminoethanol, 1-trifluoromethyl-1-cyclopropylamine,N-(2-aminoethyl)morpholine, 2-(azetidin-3-yl)acetonitrile hydrochloride,2,2-dimethylcyclopropylamine hydrochloride, 1-aminomethylcyclohexanol,aminoacetonitrile hydrochloride, 4-trifluoromethylpiperidine,3-(trifluoromethyl)azetidin-3-ol hydrochloride,tetrahydrofurylmethylamine, 2-methoxyethanamine or3-amino-1,1,1-trifluoro-2-(pyridin-3-yl)propan-2-ol obtained inReference Synthetic Example^(b) 179 were used instead of(R)-3-hydroxy-pyrrolidine to give the compounds of SyntheticExamples^(b) 113 to 132. The names, morphologies and yields of thecompounds synthesized are shown in Tables^(b) 23 and 24.

TABLE^(b) 23 Ex Compound Name Morphology Yield 1131-{trans-4-[(3-hydroxyazetidin-1-yl)methyl]cyclohexyl}- Colorless 62%1H-pyrrolo[3′,2′:5, solid (3steps) 6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione 114 1-{trans-4-[(1,1-dioxidothiomorpholino)methyl]cyclohexyl}-Colorless 33% 1H-pyrrolo[3′,2′: solid (3steps)5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)- dione 1151-{trans-4-[(4,4-difluoropiperidin-1- Colorless 68%yl)methyl]cyclohexyl}-1H-pyrrolo[3′,2′: solid (3steps)5,6]pyrido[4,3-d]pyrimidine-2,4(3H, 7H)-dione 1163,3′-({[trans-4-(2,4-dioxo-2,3,4,7-tetrahydro- Colorless 63%1H-pyrrolo[3′,2′: 5,6]pyrido[4, solid (3steps)3-d]pyrimidin-1-yl)cyclohexyl]methyl}azanediyl)dipropanenitrile 1171-(trans-4-{[(cyclopropylmethyl)amino]methyl}cyclohexyl)- Colorless 45%1H-1-pyrrolo[3′,2′: solid (3steps)5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)- dione 118(R)-1-{[trans-4-(2,4-dioxo-2,3,4,7-tetrahydro- Colorless 63%1H-pyrrolo[3′,2′:5,6]pyrido[4, solid (3steps)3-d]pyrimidin-1-yl)cyclohexyl]methyl}pyrrolidine- 3-carbonitrile 1191-{trans-4-[(3,3-dimethylazetidin-1-yl)methyl]cyclohexyl}- Brown 47%1H-pyrrolo[3′,2′: oil (3steps) 5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione 120 1-(trans-4-{[(2-hydroxyethyl)(methyl)amino]methyl}cyclohexyl)-Colorless 52% 1H-pyrrolo[3′, solid (3steps)2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H, 7H)-dione 1211-(trans-4-{[benzyl(2-hydroxyethyl)amino]methyl}cyclohexyl)- Colorless56% 1H-pyrrolo[3′, solid (3steps) 2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione 1221-[trans-4-({[1-(trifluoromethyl)cyclopropyl]amino}methyl)cyclohexyl]-Colorless 43% 1H-pyrrolo[3′, solid (3steps)2′:5,6]pyrido[4,3-d]pyrimidine- 2,4(3H,7H)-dione

TABLE^(b) 24 Ex Compound Name Morphology Yield 1231-(trans-4-{[(2-morpholinoethyl)amino]methyl}cyclohexyl)- Colorless 17%1H-pyrrolo[3′,2′:5, solid (3 steps)6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)- dione 1242-(1-{[trans-4-(2,4-dioxo-2,3,4,7-tetrahydro- Colorless  5%1H-pyrrolo[3′,2′:5,6]pyrido[4, solid (3 steps)3-d]pyrimidin-1-yl)cyclohexyl]methyl}azetidin- 3-yl)acetonitrile 1251-(trans-4-{[(2,2-dimethylcyclopropyl)amino]methyl}cyclohexyl)-Colorless 35% 1H-pyrrolo[3′, solid (3 steps)2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H, 7H)-dione 1261-[trans-4-({[(1-hydroxycyclohexyl)methyl]amino}methyl)cyclohexyl]-Colorless 23% 1H-pyrrolo[3′, solid (3 steps)2′:5,6]pyrido[4,3-d]pyrimidine- 2,4(3H,7H)-dione 1272-({[trans-4-(2,4-dioxo-2,3,4,7-tetrahydro- Colorless 46%1H-pyrrolo[3′,2′:5,6]pyrido[4,3- solid (3 steps)d]pyrimidin-1-yl)cyclohexyl]methyl}amino)acetonitrile 1281-(trans-4-{[4-(trifluoromethyl)piperidin- Colorless 70%1-yl]methyl}cyclohexyl)-1H-pyrrolo[3′, solid (3 steps)2′:5,6]pyrido[4,3-d]pyrimidine- 2,4(3H,7H)-dione 1291-(trans-4-{[3-hydroxy-3-(trifluoromethyl)azetidin- Brown 55%1-yl]methyl}cyclohexyl)- oil (3 steps)1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine- 2,4(3H,7H)-dione 1301-[trans-4-({[(tetrahydrofuran-2-yl)methyl]amino}methyl)cyclohexyl]-Colorless 72% 1H-pyrrolo[3′, solid (3 steps)2′:5,6]pyrido[4,3-d]pyrimidine- 2,4(3H,7H)-dione 1311-(trans-4-{[(2-methoxyethyl)amino]methyl}cyclohexyl)- Colorless 19%1H-pyrrolo[3′,2′:5,6]pyrido[4, solid (3 steps)3-d]pyrimidine-2,4(3H,7H)-dione 1321-[trans-4-({[3,3,3-trifluoro-2-hydroxy- Colorless 61%2-(pyridin-3-yl)propyl]amino}methyl)cyclohexyl]- solid (3 steps)1H-pyrrolo[3′,2′:5,6]pyrido[4, 3-d]pyrimidine-2,4(3H,7H)-dione

Synthetic Example^(b) 133trans-4-(2,4-Dioxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexanecarbaldehyde

1-[trans-4-(Hydroxymethyl)cyclohexyl]-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione(35.0 mg, 0.111 mmol) obtained in Synthetic Example^(b) 101 in a mixtureof toluene (1 mL) and dimethyl sulfoxide (0.25 mL) was mixed with2-iodoxybenzoic acid (37.4 mg, 0.133 mmol) and stirred at 50° C. for 2hours. The reaction mixture was allowed to cool to room temperature andstirred with saturated aqueous sodium thiosulfate and saturated aqueoussodium hydrogen carbonate at room temperature for 30 minutes. Theprecipitated solid was collected by filtration to give the titlecompound as a colorless solid (26.7 mg, yield 77%).

Synthetic Example^(b) 1343-[trans-4-(2,4-Dioxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexyl]propanenitrile

3-[trans-4-(2,4-Dioxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexyl]acrylonitrile(16.2 mg, 0.0347 mmol) obtained in Reference Synthetic Example^(b) 170in tetrahydrofuran (1.0 mL) was stirred with 5% palladium-carbon (10 mg)at room temperature for 1 day under a hydrogen atmosphere. The reactionmixture was filtered, and the filtrate was concentrated under reducedpressure. The resulting residue was dissolved in dichloromethane (1.0mL) and stirred with trifluoroacetic acid (0.4 mL) at room temperaturefor 5 hours. The reaction mixture was concentrated under reducedpressure, and the resulting residue was stirred with methanol (0.7 mL),ethylenediamine (30 μL) and 1 M aqueous sodium hydroxide (30 μL) at roomtemperature for 1 day. The reaction mixture was filtered, and theresulting solid was washed with water and methanol to give the titlecompound as a colorless solid (2.73 mg, yield 25% (three steps)).

Synthetic Example^(b) 1352-Cyano-N-{[trans-4-(2,4-dioxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexyl]methyl}-N-(2,2,2-trifluoroethyl)acetamide

1-(4-{[(2,2,2-Trifluoroethyl)amino]methyl}cyclohexyl)-7{[-2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione(25.0 mg, 0.048 mmol) obtained in Reference Synthetic Example^(b) 169 inN,N-dimethylformamide (1 mL) was stirred with 2-cyanoacetic acid (10 mg,0.071 mmol), 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (27 mg, 0.071 mmol) and N,N-diisopropylethylamine(16 μL, 0.095 mmol) at room temperature for 3 days. After addition ofsaturated aqueous sodium hydrogen carbonate, the reaction mixture wasextracted with chloroform, and the organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography(chloroform/methanol=19/1 (v/v)) to give the compound as a yellow oil.The resulting yellow oil was dissolved in dichloromethane (1.0 mL) andstirred with trifluoroacetic acid (150 μL) at room temperature for 1day. The reaction mixture was concentrated under reduced pressure, andthe resulting residue was stirred with methanol (1 mL), ethylenediamine(50 μL) and 1 M aqueous sodium hydroxide (50 μL) at room temperature for1 day. The precipitated solid was collected by filtration to give thetitle compound as a colorless solid (2.70 mg, yield 14%(three steps)).

Synthetic Example^(b) 1361-(trans-4-{[Methyl(2,2,2-trifluoroethyl)amino]methyl}cyclohexyl)-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione

1-(4-{[(2,2,2-Trifluoroethyl)amino]methyl}cyclohexyl)-7{[-2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione(30 mg, 0.048 mol) obtained in Reference Synthetic Example^(b) 169 in amixture of methanol (1 mL) and acetic acid (100 μL) was stirred withformaldehyde solution (37%) (20 μL) and 2-picoline borane (15 mg, 0.14mmol) at room temperature for 3 days. After addition of saturatedaqueous ammonium chloride, the reaction mixture was extracted withchloroform, and the organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography(chloroform/methanol=19/1 (v/v)) to give the compound as a colorlesssolid. The resulting colorless solid was dissolved in dichloromethane (1mL) and stirred with trifluoroacetic acid (150 μL) at room temperaturefor 1 day. The reaction mixture was concentrated under reduced pressure,and the resulting residue was stirred with methanol (1 mL),ethylenediamine (50 μL) and 1 M aqueous sodium hydroxide (50 μL) at roomtemperature for 1 day. The precipitated solid was collected byfiltration to give the title compound as a colorless solid (24.95 mg,quantitative yield (three steps)).

Synthetic Example^(b) 1372-(1-Cyclohexyl-2,4-dioxo-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-3(2H,4H,7H)-yl)acetonitrile

1-Cyclohexyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione(20 mg, 0.048 mmol) obtained in Reference Synthetic Example^(b) 95 inN,N-dimethylformamide (1 mL) was mixed with potassium carbonate (10 mg,0.072 mmol) and 2-chloroacetonitrile (5.0 μL, 0.072 mmol) and stirred at80° C. for 1 day. After addition of saturated aqueous ammonium chloride,the reaction mixture was extracted with chloroform, and the organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane=1/4→1/3 (v/v)) to give the compoundas a yellow oil. The resulting yellow oil was dissolved indichloromethane (1 mL) and stirred with trifluoroacetic acid (150 μL) atroom temperature for 1 day. The reaction mixture was concentrated underreduced pressure, and the resulting residue was stirred with methanol (1mL), ethylenediamine (50 μL) and 1 M aqueous sodium hydroxide (50 μL) atroom temperature for 1 day. The precipitated solid was collected byfiltration to give the title compound as a colorless solid (24.5 mg,yield 79%(three steps)).

Synthetic Examples^(b) 138 to 154

The reactions in Synthetic Example^(b) 137 were carried out insubstantially the same manners except that iodomethane,2,2,2-trifluoroethyl trifluoromethanesulfonate, 2-bromoethanol,3-bromopropan-1-ol, 4-(2-chloroethyl)morpholine hydrochloride,chloro(methoxy)methane, 1-bromo-4-fluorobutane, 1-bromo-2-methoxyethane,2-bromopropanenitrile, (chloromethyl)(methyl)sulfane, bromocyclopentane,(bromomethyl)cyclopropane, 2-(bromomethyl)tetrahydrofuran,3-(chloromethyl)-3-methyloxetane, 2-chloro-N,N-dimethylacetamide,2-chloro-N,N-dimethylethanamine hydrochloride or tert-butyl4-bromopiperidine-1-carboxylate were used instead of2-chloroacetonitrile to give the compounds of Synthetic Examples^(b) 138to 154. The names, morphologies and yields of the compounds synthesizedare shown in Tables^(b) 25 and 26.

TABLE^(b) 25 Ex Compound Name Morphology Yield 1381-cyclohexyl-3-methyl-1H-pyrrolo[3′, Colorless solid 59%2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H, 7H)-dione (3 steps) 1391-cyclohexyl-3-(2,2,2-trifluoroethyl)- Colorless 49%1H-pyrrolo[3′,2′:5,6]pyrido[4,3- solid (3 steps)d]pyrimidine-2,4(3H,7H)-dione 140 1-cyclohexyl-3-(2-hydroxyethyl)-1H-Colorless 61% pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine- solid (3 steps)2,4(3H,7H)-dione 141 1-cyclohexyl-3-(3-hydroxypropyl)-1H- Colorless 31%pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine- solid (3 steps)2,4(3H,7H)-dione 142 1-cyclohexyl-3-(2-morpholinoethyl)- Colorless 68%1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine- solid (3 steps)2,4(3H,7H)-dione 143 1-cyclohexyl-3-(methoxymethyl)-1H-pyrrolo[3′,Colorless 49% 2′:5,6]pyrido[4,3-d]pyrimidine- solid (3 steps)2,4(3H,7H)-dione 144 1-cyclohexyl-3-(4-fluorobutyl)-1H-pyrrolo[3′,Colorless 55% 2′:5,6]pyrido[4,3-d]pyrimidine- solid (3 steps)2,4(3H,7H)-dione 145 1-cyclohexyl-3-(2-methoxyethyl)-1H- Colorless 60%pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine- solid (3 steps)2,4(3H,7H)-dione 146 2-(1-cyclohexyl-2,4-dioxo-1H-pyrrolo[3′, Colorless72% 2′:5,6]pyrido[4,3-d]pyrimidin- solid (3 steps)3(2H,4H,7H)-yl)propanenitrile 147 1-cyclohexyl-3-[(methylthio)methyl]-Colorless 80% 1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine- solid (3steps) 2,4(3H,7H)-dione

TABLE^(b) 26 Mor- Ex Compound Name phology Yield 1481-cyclohexyl-3-cyclopentyl-1H-pyrrolo[3′, Colorless 55%2′:5,6]pyrido[4,3-d]pyrimidine- solid (3 steps) 2,4(3H,7H)-dione 1491-cyclohexyl-3-(cyclopropylmethyl)- Colorless 99%1H-pyrrolo[3′,2′:5,6]pyrido[4,3- solid (3 steps)d]pyrimidine-2,4(3H,7H)-dione 150 1-cyclohexyl-3-[(tetrahydrofuran-2-Colorless 83% yl)methyl]-1H-pyrrolo[3′,2′:5,6]pyrido[4, solid (3 steps)3-d]pyrimidine-2,4(3H,7H)-dione 151 1-cyclohexyl-3-[3-hydroxy-2-Colorless 56% (hydroxymethyl)-2-methylpropyl]- solid (3 steps)1H-pyrrolo[3′, 2′:5,6]pyrido[4,3- d]pyrimidine-2,4(3H,7H)-dione 1522-(1-cyclohexyl-2,4-dioxo-1H-pyrrolo[3′, Colorless 64%2′:5,6]pyrido[4,3-d]pyrimidin- solid (3 steps)3(2H,4H,7H)-yl)-N,N-dimethylacetamide 1531-cyclohexyl-3-[2-(dimethylamino)ethyl]- Colorless 30%1H-pyrrolo[3′,2′:5,6]pyrido[4, solid (3 steps)3-d]pyrimidine-2,4(3H,7H)-dione 154 1-cyclohexyl-3-(piperidin-4-yl)-1H-Colorless 15% pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine- solid (3 steps)2,4(3H,7H)-dione

Synthetic Example^(b) 155N-{[trans-4-(2,4-Dioxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexyl]methyl}-3,3,3-trifluoro-N-(2,2,2-trifluoroethyl)propanamide

The reactions in Synthetic Example^(b) 135 were carried out insubstantially the same manners except that 3,3,3-trifluoropropanoic acidwas used instead of 2-cyanoacetic acid to give the title compound as acolorless solid (1.95 mg, yield 8% (three steps)).

The structural formulae of the compounds obtained the ReferenceSynthetic Examples^(b) and Synthetic Examples^(b) are shown below inTables^(b) 27 to 44. The physical property data on the compoundsobtained the Reference Synthetic Examples^(b) and Synthetic Examples^(b)are shown below in Tables^(b) 45 to 77.

TABLE^(b) 27 Rf Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

TABLE^(b) 28 Rf Structure 25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

TABLE^(b) 29 Rf Structure 49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

TABLE^(b) 30 Rf Structure 70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

  86a

 86b

87

88

89

TABLE^(b) 31 Rf Structure 90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

TABLE^(b) 32 Rf Structure 111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

TABLE^(b) 33 Rf Structure 132

133

134

135

136

137

138

139

140

141

142

143

144

TABLE^(b) 34 Rf Structure 145

146

147

148

149

150

151

152

153

154

155

156

157

158

  159a

 159b

160

161

162

163

164

165

166

167

168

169

170

TABLE^(b) 35 Rf Structure 171

172

173

174

175

176

177

178

179

TABLE^(b) 36 Ex Structure  1

 2

 3

 4

 5

   6a

 6b

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

TABLE^(b) 37 Ex Structure 21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

TABLE^(b) 38 Ex Structure 42

43

44

45

46

47

  48a

 48b

49

50

51

52

53

54

55

56

57

58

59

60

61

TABLE^(b) 39 Ex Structure 62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

TABLE^(b) 40 Ex Structure 83

84

85

86

87

TABLE^(b) 41 Ex Structure 88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

TABLE^(b) 42 Ex Structure 109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

TABLE^(b) 43 Ex Structure 130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

TABLE^(b) 44 Ex Structure 148

149

150

151

152

153

154

155

TABLE^(b) 45 Rf Data 1 ¹H-NMR (CD₃OD) δ: 3.31 (s, 3H), 3.76 (s, 3H),7.28 (d, J = 5.36 Hz, 1H), 8.18 (d, J = 4.76 Hz, 1H), 8.57 (s, 1H).LC/MS: condition 1, retention time = 0.54 min LC/MS (ESI⁺) m/z; 167 [M +H]⁺ 2 ¹H-NMR (CDCl₃) δ: 0.98 (d, J = 6.5 Hz, 3H), 1.56-1.83 (m, 3H),2.20-2.35 (m, 1H), 2.61-2.85 (m, 1H), 3.31 (d, J = 10.9 Hz, 1H), 3.53(d, J = 14.9 Hz, 1H), 3.67 (s, 3H), 4.02 (dd, J = 13.0, 5.4, 1H),4.13-4.26 (m, 2H), 7.47 (d, J = 2.4 Hz, 2H), 7.55 (d, J = 2.38 Hz, 3H),12.4 (bs, 1H). LC/MS: condition 1, retention time = 0.51 min LC/MS(ESI⁺) m/z; 263 [M + H]⁺ 3 ¹H-NMR (CDCl₃) δ: 0.92 (d, 3H), 1.41-1.53 (m,3H), 1.90-2.18 (m, 2H), 2.65-2.89 (m, 3H), 3.46 (s, 2H), 7.18-7.40 (m,5H). LC/MS: condition 1, retention time = 0.47 min LC/MS (ESI⁺) m/z; 205[M + H]⁺ 4 ¹H-NMR (CDCl₃) δ: 6.55 (d, J = 3.3 Hz, 1H), 7.06 (dd, J =8.0, 6.3 Hz, 1H), 7.43 (d, J = 3.3 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H),8.26 (d, J = 6.3 Hz, 1H). LC/MS: condition 1, retention time = 0.64 minLC/MS (ESI⁺) m/z; 135.0 [M + H]⁺ 5 ¹H-NMR (CDCl₃) δ: 6.63 (d, J = 3.6Hz, 1H), 7.14 (d, J = 5.2 Hz, 1H), 7.39 (d, J = 3.6 Hz, 1H), 8.22 (d, J= 5.2 Hz, 1H), 10.4 (br s, 1H). LC/MS: condition 1, retention time =3.16 min LC/MS (ESI⁺) m/z; 153, 155 [M + H]⁺ 6 ¹H-NMR (CDCl₃) δ: 1.11(d, J = 7.5 Hz, 18H), 1.84 (septet, J = 7.5 Hz, 3H), 6.65 (d, J = 3.6Hz, 1H), 7.06 (d, J = 5.2 Hz, 1H), 7.33 (d, J = 3.6 Hz, 1H), 7.75 (d, J= 5.2 Hz, 1H). LC/MS: condition 1, retention time = 6.91 min LC/MS(ESI⁺) m/z; 309, 311 [M + H]⁺ 7 ¹H-NMR (DMSO-d₆) δ: 6.73 (dd, J = 3.6,2.1 Hz, 1H), 7.75 (br t, J = 3.0 Hz, 1H), 8.68 (s, 1H), 10.4 (s, 1H),12.5 (bs, 1H). LC/MS: condition 1, retention time = 3.19 min LC/MS(ESI⁺) m/z; 181, 183 [M + H]⁺ LC/MS (ESI) m/z; 179, 181 [M − H] 8 ¹H-NMR(CDCl₃) δ: 1.29-1.56 (m, 4H), 1.60-1.75 (m, 2H), 1.78-1.92 (m, 2H),2.07-2.20 (m, 2H), 3.94-4.06 (m, 1H), 6.59 (d, J = 3.6 Hz, 1H), 7.10 (d,J = 3.6 Hz, 1H), 8.20 (s, 1H), 9.62 (br d, J = 7.6 Hz, 1H), 9.80 (s,1H), 11.0 (br s, 1H). LC/MS: condition 1, retention time = 3.02 minLC/MS (ESI⁺) m/z; 244 [M + H]⁺ 9 ¹H-NMR (CDCl₃) δ: −0.05 (s, 9H), 0.91(t, J = 8.5 Hz, 2H), 1.25-1.75 (m, 6H), 1.75-1.90 (m, 2H), 2.07-2.20 (m,2H), 3.54 (t, J = 8.5 Hz, 2H), 3.90-4.05 (m, 1H), 5.61 (s, 2H), 6.60 (d,J = 3.8 Hz, 1H), 7.09 (d, J = 3.8 Hz, 1H), 8.18 (s, 1H), 9.58 (br d, J =7.7 Hz, 1H), 9.80 (s, 1H). LC/MS: condition 1, retention time = 5.22 minLC/MS (ESI⁺) m/z; 374 [M + H]⁺

TABLE^(b) 46 Rf Data 11 ¹H-NMR (CDCl₃) δ: −0.06 (s, 9H), 0.90-1.00 (m,2H), 1.10-1.80 (m, 6H), 1.80-1.95 (m, 2H), 1.95-2.10 (m, 2H), 3.50-3.60(m, 2H), 3.90-4.10 (m, 1H), 4.76 (s, 2H), 4.96 (s, 2H), 5.62 (s, 2H),6.43 (d, J = 3.6 Hz, 1H), 7.20 (d, J = 3.6 Hz, 1H), 7.82 (s, 1H). LC/MS:condition 1, retention time = 3.86 min LC/MS (ESI⁺) m/z; 388 [M + H]⁺ 12¹H-NMR (CDCl₃) δ: −0.06 (s, 9H), 0.90 (t, J = 8.3 Hz, 2H), 1.37-1.54 (m,6H), 1.74-1.92 (m, 2H), 2.02-2.24 (m, 2H), 3.54 (t, J = 8.0 Hz, 2H),3.83-4.04 (m, 3H), 5.58, (s, 2H), 6.52 (d, J = 3.9 Hz, 1H), 6.74-6.94(m, 1H), 7.08 (d, J = 3.3 Hz, 1H), 7.79 (s, 1H). LC/MS: condition 1,retention time = 3.02 min LC/MS (ESI⁺) m/z; 375 [M + H]⁺ 13 ¹H-NMR(CDCl₃) δ: −0.05 (s, 9H), 0.92, (t, J = 8.3 Hz, 2H), 1.23-1.50 (m, 3H),1.57-1.84 (m, 2H), 1.84-2.02 (m, 3H), 2.63-2.67 (m, 2H), 3.54 (t, J =8.0 Hz, 2H), 4.00-4.23 (m, 1H), 4.36 (d, J = 2.1 Hz, 2H), 5.20 (s, 1H),5.65 (s, 2H), 6.49 (d, J = 3.6 Hz, 1H), 7.30 (d, J = 3.9 Hz 1H), 7.97(s, 1H). LC/MS: condition 1, retention time = 4.79 min LC/MS (ESI⁺) m/z;401 [M + H]⁺ 14 LC/MS: condition 1, retention time = 3.46 min LC/MS(ESI⁺) m/z; 385 [M + H]⁺ 15 ¹H-NMR (CDCl₃) δ: 3.06 (t, J = 8.1 Hz, 2H),3.61 (t, J = 8.1 Hz, 2H), 4.48 (br s, 1H), 6.50 (dd, J = 5.4, 6.9 Hz,1H), 7.24 (d, J = 6.9 Hz, 1H), 7.81 (d, J = 5.4 Hz, 1H). LC/MS:condition 1, retention time = 0.50 min LC/MS (ESI⁺) m/z; 121 [M + H]⁺ 16¹H-NMR (CDCl₃) δ: 3.07 (t, J = 8.4 Hz, 2H), 3.65 (t, J = 8.1 Hz, 2H),4.50 (br s, 1H), 7.32 (s, 1H), 7.85 (s, 1H). LC/MS: condition 1,retention time = 0.52 min LC/MS (ESI⁺) m/z; 199, 201 [M + H]⁺ 17 ¹H-NMR(CDCl₃) δ: 6.40-6.50 (m, 1H), 7.30-7.40 (m, 1H), 8.07 (d, J = 2.1 Hz,1H), 8.35 (d, J = 1.5 Hz, 1H), 9.50 (br s, 1H). LC/MS: condition 1,retention time = 3.52 min LC/MS (ESI⁺) m/z; 197, 199 [M + H]⁺ 18 LC/MS:condition 1, retention time = 1.36 min LC/MS (ESI⁺) m/z; 213, 215 [M +H]⁺ 19 ¹H-NMR (CDCl₃) δ: −0.06 (s, 9H), 0.90 (t, J = 8.1 Hz, 2H), 3.52(t, J = 7.8 Hz, 2H), 5.63 (s, 2H), 6.60 (d, J = 3.6 Hz, 1H), 7.38 (d, J= 3.6 Hz, 1H), 8.41 (s, 1H). LC/MS: condition 1, retention time = 5.54min LC/MS (ESI⁺) m/z; 361, 363, 365 [M + H]⁺ 20 ¹H-NMR (CDCl₃) δ: −0.06(s, 9H), 0.90 (t, J = 8.1 Hz, 2H), 1.30-1.70 (m, 6H), 1.80-1.90 (m, 2H),2.10-2.20 (m, 2H), 3.53 (t, J = 8.1 Hz, 2H), 3.90-4.00 (m, 1H), 4.97 (d,J = 8.4 Hz, 1H), 5.58 (s, 2H), 6.51 (d, J = 3.6 Hz, 1H), 7.12 (d, J =3.9 Hz, 1H), 8.11 (s, 1H). LC/MS: condition 1, retention time = 5.42 minLC/MS (ESI⁺) m/z; 424, 426 [M + H]⁺

TABLE^(b) 47 Rf Data 21 LC/MS: condition 1, retention time = 5.01 minLC/MS (ESI⁺) m/z; 388 [M + H]⁺ 23 LC/MS: condition 1, retention time =4.01 min LC/MS (ESI⁺) m/z; 402 [M + H]⁺ 24 ¹H-NMR (CDCl₃) δ: −0.06 (s,9H), 0.93 (t, J = 8.1 Hz, 2H), 1.50-1.95 (m, 6H), 2.00-2.15 (m, 2H),2.20-2.30 (m, 2H), 3.56 (t, J = 8.1 Hz, 2H), 4.85-5.00 (m, 1H), 5.80 (s,2H), 6.43 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 3.6 Hz, 1H), 7.43 (d, J =3.9 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 9.41 (s, 1H). LC/MS: condition 1,retention time = 4.64 min LC/MS (ESI⁺) m/z; 398 [M + H]⁺ 25 LC/MS:condition 1, retention time = 5.46 min LC/MS (ESI⁺) m/z; 387, 389 [M +H]⁺ 26 ¹H-NMR (CDCl₃) δ: 1.30-1.60 (m, 4H), 1.60-1.80 (m, 2H), 1.80-1.95(m, 2H), 2.10-2.25 (m, 2H), 3.07 (s, 3H), 3.95-4.10 (m, 1H), 6.61 (d, J= 3.3 Hz, 1H), 7.15-7.25 (m, 2H), 8.54 (s, 1H), 11.82 (br s, 1H). LC/MS:condition 1, retention time = 3.31 min LC/MS (ESI⁺) m/z; 294 [M + H]⁺ 28LC/MS: condition 1, retention time = 4.87 min LC/MS (ESI⁺) m/z; 434 [M +H]⁺ 29 LC/MS: condition 1, retention time = 4.26 min LC/MS (ESI+) m/z;390 [M + 1]+ LC/MS (ESI−) m/z; 388 [M − 1]− 30 ¹H-NMR (CDCl₃) δ: −0.05(s, 9H), 0.91 (t, J = 8.1 Hz, 2H), 1.35-1.45 (m, 5H), 1.60-1.70 (m, 1H),1.75-1.90 (m, 2H), 2.05-2.20 (m, 2H), 3.54 (t, J = 7.8 Hz, 2H),3.90-4.05 (m, 1H), 5.58 (s, 2H), 5.55-5.70 (m, 2H), 6.59 (d, J = 3.6 Hz,1H), 7.08 (d, J = 3.9 Hz, 1H), 8.29 (s, 1H), 9.32 (d, J = 7.5 Hz, 1H).LC/MS: condition 1, retention time = 4.02 min LC/MS (ESI⁺) m/z; 389 [M +H]⁺ 31 LC/MS: condition 1, retention time = 4.97 min LC/MS (ESI⁺) m/z;417 [M + H]⁺ 32 ¹H-NMR (CDCl₃) δ: −0.06 (s, 9H), 0.93 (t, J = 8.1 Hz,2H), 1.50-2.00 (m, 6H), 2.00-2.15 (m, 2H), 2.20-2.40 (m, 2H), 3.56 (t, J= 8.1 Hz, 2H), 4.70-4.85 (m, 1H), 5.79 (s, 2H), 6.77 (d, J = 4.2 Hz,1H), 7.51 (d, J = 3.9 Hz, 1H), 8.50 (s, 1H), 9.32 (s, 1H). LC/MS:condition 1, retention time = 4.42 min LC/MS (ESI⁺) m/z; 399 [M + H]⁺ 33¹H-NMR (CDCl₃) δ: −0.06 (s, 9H), 0.85-1.00 (m, 2H), 2.76 (s, 3H),3.50-3.60 (m, 2H), 5.68 (s, 2H), 6.74 (d, J = 3.6 Hz, 1H), 7.44 (s, J =3.6 Hz, 1H), 8.66 (s, 1H). LC/MS: condition 1, retention time = 4.87 minLC/MS (ESI⁺) m/z; 325, 327 [M + H]⁺

TABLE^(b) 48 Rf Data 34 ¹H-NMR (CDCl₃) δ: −0.06 (s, 9H), 0.90 (t, J =8.1 Hz, 2H), 0.98 (d, J = 6.6 Hz, 3H), 1.60-1.85 (m, 2H), 1.90-2.00 (m,1H), 2.20-2.30 (m, 1H), 2.25-2.35 (m, 1H), 2.67 (s, 3H), 2.70-2.90 (m,2H), 3.45-3.60 (m, 4H), 4.30-4.40 (m, 1H), 5.57 (s, 2H), 6.58 (d, J =3.6 Hz, 1H), 7.00 (d, J = 3.9 Hz, 1H), 7.10-7.40 (m, 5H), 8.66 (s, 1H),10.70 (d, J = 9.9 Hz, 1H). 35 ¹H-NMR (CDCl₃) δ: −0.08 (s, 9H), 0.86 (d,J = 6.9 Hz, 3H), 0.91 (t, J = 8.1 Hz, 2H), 1.70-2.00 (m, 2H), 2.40-2.60(m, 2H), 2.75-2.90 (m, 2H), 2.95-3.05 (m, 1H), 3.50-3.65 (m, 4H),5.35-5.45 (m, 1H), 5.78 (dd, J = 10.5, 15.0 Hz, 2H), 6.39 (d, J = 8.1Hz, 1H), 6.81 (d, J = 3.9 Hz, 1H), 7.25-7.40 (m, 5H), 7.41 (d, J = 3.6Hz, 1H), 8.54 (br s, 1H), 9.41 (s, 1H). LC/MS: condition 1, retentiontime = 3.59 min LC/MS (ESI⁺) m/z; 503 [M + H]⁺ 36 LC/MS: condition 1,retention time = 3.06 min LC/MS (ESI⁺) m/z; 413 [M + H]⁺ 37 ¹H-NMR(CDCl₃) δ: −0.06 (s, 9H), 0.93 (t, J = 8.1 Hz, 2H), 1.02 (d, J = 7.5 Hz,3H), 1.14 (d, J = 6.6 Hz, 6H), 1.80-1.90 (m, 1H), 2.15-2.45 (m, 2H),2.65-2.80 (m, 1H), 2.87 (d, J = 6.6 Hz, 2H), 3.15-3.35 (m, 1H), 3.56 (t,J = 8.1 Hz, 2H), 3.55-3.75 (m, 2H), 3.85-3.95 (m, 1H), 5.35-5.45 (m,1H), 5.80 (s, 2H), 6.40 (d, J = 7.8 Hz, 1H), 6.75 (d, J = 3.6 Hz, 1H),7.46 (d, J = 3.9 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 9.42 (s, 1H). LC/MS:condition 1, retention time = 4.52 min LC/MS (ESI⁺) m/z; 533 [M + H]⁺LC/MS (ESI⁻) m/z; 577 [M + HCOO]⁻ 38 LC/MS: condition 1, retention time= 0.54 min LC/MS (ESI⁺) m/z; 349 [M + H]⁺ 39 ¹H-NMR (CDCl₃) δ: −0.06 (s,9H), 0.87-0.95 (m, 2H), 0.98 (d, J = 6.9 Hz, 3H), 1.59-1.80 (m, 2H),1.87-2.04 (m, 1H), 2.14-2.24 (m, 1H), 2.38-2.41 (m, 1H), 2.85-2.89 (m,2H), 3.47-3.62 (m, 4H), 4.28-4.39 (m, 1H), 5.59 (s, 2H), 6.59 (d, J =3.6 Hz, 1H), 7.04 (d, J = 3.9 Hz, 1H), 7.17-7.39 (m, 5H), 8.20 (s, 1H),9.87 (s, 1H), 10.0 (d, J = 9.5 Hz, 1H). LC/MS: condition 1, retentiontime = 3.57 min LC/MS (ESI⁺) m/z; 479 [M + H]⁺ 40 ¹H-NMR (CDCl₃) δ:−0.07 (s, 9H), 0.86-0.92 (m, 2H), 1.01 (d, J = 6.6 Hz, 3H), 1.43-1.96(m, 3H), 2.07-2.14 (m, 1H), 2.25-2.28 (m, 1H), 2.78-2.93 (m, 2H),3.46-3.55 (m, 4H), 4.20-4.31 (m, 1H), 4.77 (dd, J = 20.8, 12.2 Hz, 2H),5.57 (s, 2H), 5.95 (d, J = 9.8 Hz, 1H), 6.51 (d, J = 3.6 Hz, 1H), 7.07(d, J = 3.6 Hz, 1H), 7.18-7.29 (m, 5H), 7.87 (s, 1H). LC/MS: condition1, retention time = 3.04 min LC/MS (ESI⁺) m/z; 481 [M + H]⁺ 41 LC/MS:condition 1, retention time = 2.91 min LC/MS (ESI⁺) m/z; 363 [M + H −SEM]⁺ 42 ¹H-NMR (DMSO-d₆) δ: 8.30 (br s, 1H), 8.44 (s, 1H), 8.49 (s,1H). LC/MS: condition 1, retention time = 0.89 min LC/MS (ESI⁺) m/z;198, 200 [M + H]⁺ LC/MS (ESI⁻) m/z; 196, 198 [M − H]⁻

TABLE^(b) 49 Rf Data 43 LC/MS: condition 1, retention time = 0.54 minLC/MS (ESI⁺) m/z; 214, 216 [M + H]⁺ 44 ¹H-NMR (DMSO-d₆) δ: 8.50 (s, 1H),8.56 (s, 1H), 8.57 (d, J = 1.8 Hz, 1H). LC/MS: condition 1, retentiontime = 2.74 min LC/MS (ESI⁺) m/z; 232, 234, 236 [M + H]⁺ LC/MS (ESI⁻)m/z; 230, 232, 234 [M − H]⁻ 46 ¹H-NMR (CDCl₃) δ: −0.04 (s, 9H), 0.94 (t,J = 8.4 Hz, 2H), 2.79 (s, 3H), 3.62 (t, J = 8.4 Hz, 2H), 5.69 (s, 2H),8.30 (s, 1H), 8.73 (s, 1H). LC/MS: condition 1, retention time = 4.31min LC/MS (ESI⁺) m/z; 326, 328 [M + H]⁺ 47 ¹H-NMR (CDCl₃) δ: −0.03 (s,9H), 0.93 (t, J = 8.4 Hz, 2H), 1.22-1.78 (m, 6H), 1.78-1.90 (m, 2H),2.03-2.18 (m, 2H), 2.63 (s, 3H), 3.61 (t, J = 8.4 Hz, 2H), 4.87-5.03 (m,1H), 5.58 (s, 2H), 7.88 (s, 1H), 8.69 (s, 1H), 10.10 (br s, 1H). LC/MS:condition 1, retention time = 5.19 min LC/MS (ESI⁺) m/z; 389 [M + H]⁺ 48¹H-NMR (CDCl₃) δ: −0.04 (s, 9H), 0.95 (t, J = 8.4 Hz, 2H), 1.20-1.38 (m,1H), 1.58-2.24 (m, 9H), 3.65 (t, J = 8.4 Hz, 2H), 5.77 (s, 2H), 6.46 (d,J = 8.0 Hz, 1H), 6.40-6.55 (m, 1H), 7.81 (d, J = 8.0 Hz, 1H), 8.16 (s,1H), 9.47 (s, 1H). LC/MS: condition 1, retention time = 4.66 min LC/MS(ESI⁺) m/z; 399 [M + H]⁺

TABLE^(b) 50 Rf Data 49 ¹H-NMR (CDCl₃) δ: −0.04 (s, 9H), 0.92 (t, J =8.4 Hz, 2H), 2.74 (s, 3H), 3.53 (t, J = 8.7 Hz, 2H), 5.64 (s, 2H), 7.48(s, 1H), 8.54 (s, 1H). LC/MS: condition 1, retention time = 5.19 minLC/MS (ESI⁺) m/z; 403, 405 [M + H]⁺ 50 ¹H-NMR (CDCl₃) δ: −0.07 (s, 9H),0.72 (d, J = 6.3 Hz, 3H), 0.96 (t, J = 8.1 Hz, 2H), 1.45-1.60 (m, 1H),1.70-1.90 (m, 2H), 2.05-2.18 (m, 1H), 2.31-2.42 (m, 1H), 2.71 (s, 3H),2.88-3.00 (m, 1H), 3.10-3.22 (m, 1H), 3.51-3.69 (m, 4H), 4.60-4.80 (m,1H), 5.61 (dd, J = 10.8, 16.2 Hz, 2H), 7.21-7.43 (m, 6H), 8.65 (s, 1H).LC/MS: condition 1, retention time = 3.86 min LC/MS (ESI⁺) m/z; 571, 573[M + H]⁺ 51 ¹H-NMR (CDCl₃) δ: −0.08 (s, 9H), 0.20 (d, J = 6.9 Hz, 3H),0.90 (t, J = 8.7 Hz, 2H), 1.40-1.52 (m, 1H), 1.62-1.72 (m, 1H),1.82-2.00 (m, 1H), 2.05-2.20 (m, 1H), 2.70-2.82 (m, 1H), 3.02-3.17 (m,1H), 3.50-3.60 (m, 4H), 3.60-3.71 (m, 1H), 5.40-5.50 (m, 1H), 5.74 (dd,J = 13.8, 10.5 Hz, 2H), 6.44 (d, J = 7.8 Hz, 1H), 7.20-7.45 (m, 5H),7.47 (s, 1H), 9.34 (s, 1H), 9.49 (d, J = 7.8 Hz, 1H). LC/MS: condition1, retention time = 4.89 min LC/MS (ESI⁺) m/z; 581, 583 [M + H]⁺ 52¹H-NMR (CDCl₃) δ: −0.05 (s, 9H), 0.91 (t, J = 8.4 Hz, 2H), 2.74 (s, 3H),3.52 (t, J = 8.1 Hz, 2H), 5.63 (s, 2H), 7.40 (s, 1H), 8.54 (s, 1H).LC/MS: condition 1, retention time = 5.00 min LC/MS (ESI⁺) m/z; 359, 361[M + H]⁺ 53 LC/MS: condition 1, retention time = 3.67 min LC/MS (ESI⁺)m/z; 527, 529 [M + H]⁺ 54 ¹H-NMR (CDCl₃) δ: −0.10 (s, 9H), 0.27 (d, J =6.9 Hz, 3H), 0.90 (t, J = 8.4 Hz, 2H), 1.41-1.56 (m, 1H), 1.60-1.80 (m,1H), 1.86-2.03 (m, 1H), 2.06-2.20 (m, 1H), 2.68-2.80 (m, 1H), 3.05-3.20(m, 1H), 3.50-3.70 (m, 5H), 5.35-5.42 (m, 1H), 5.74 (s, 2H), 6.44 (d, J= 8.1 Hz, 1H), 7.22-7.48 (m, 6H), 9.34 (s, 1H), 9.45 (d, J = 8.1 Hz,1H). LC/MS: condition 1, retention time = 4.60 min LC/MS (ESI⁺) m/z;537, 539 [M + H]⁺ 55 LC/MS: condition 1, retention time = 4.79 min LC/MS(ESI⁺) m/z; 311, 313 [M + H]⁺ 56 ¹H-NMR (CDCl₃) δ: −0.07 (s, 9H), 0.90(t, J = 8.4 Hz, 2H), 1.00 (t, J = 7.2 Hz, 3H), 1.91 (quint, J = 7.2 Hz,2H), 3.53 (t, J = 8.4 Hz, 2H), 5.10-5.20 (m, 1H), 5.65 (s, 2H), 6.60 (d,J = 3.6 Hz, 1H), 7.36 (d, J = 3.6 Hz, 1H), 8.45 (s, 1H). LC/MS:condition 1, retention time = 4.81 min LC/MS (ESI⁺) m/z; 341, 343 [M +H]⁺ 57 LC/MS: condition 1, retention time = 5.21 min LC/MS (ESI⁺) m/z;339, 341 [M + H]⁺ 58 LC/MS: condition 1, retention time = 3.71 min LC/MS(ESI⁺) m/z; 507 [M + H]⁺

TABLE^(b) 51 Rf Data 59 ¹H-NMR (CDCl₃) δ: −0.10 (s, 9H), 0.85 (d, J =7.2 Hz, 3H), 0.90 (t, J = 9.0 Hz, 2H), 1.70-1.85 (m, 1H), 1.85-2.00 (m,1H), 2.19 (s, 3H), 2.35-2.58 (m, 2H), 2.75-2.90 (m, 2H), 3.00-3.12 (m,1H), 3.50-3.70 (m, 4H), 5.33-5.41 (m, 1H), 5.77 (dd, J = 9.9, 15.0 Hz,2H), 6.79 (d, J = 3.6 Hz, 1H), 7.20-7.40 (m, 6H), 8.51 (br s, 1H), 9.45(s, 1H). LC/MS: condition 1, retention time = 3.74 min LC/MS (ESI⁺) m/z;517 [M + H]⁺ 60 LC/MS: condition 1, retention time = 4.24 min LC/MS(ESI⁺) m/z; 581, 583 [M + H]⁺ 61 ¹H-NMR (CDCl₃) δ: −0.05 (s, 9H),0.85-0.95 (m, 2H), 0.99 (d, J = 7.5 Hz, 3H), 1.85-1.95 (m, 1H),2.25-2.35 (m, 1H), 2.65-2.75 (m, 1H), 3.35-3.45 (m, 1H), 3.58 (t, J =8.1 Hz, 2H), 3.65-3.85 (m, 2H), 3.90-4.00 (m, 1H), 5.40-5.50 (m, 1H),5.80 (s, 2H), 6.36 (d, J = 8.1 Hz, 1H), 6.75 (d, J = 3.6 Hz, 1H), 7.46(d, J = 3.6 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.70-7.85 (m, 2H),7.90-7.95 (m, 1H), 8.10-8.15 (m, 1H), 9.40 (s, 1H). LC/MS: condition 3,retention time = 2.56 min LC/MS (ESI⁺) m/z; 578 [M + H]⁺ 62 ¹H-NMR(CDCl₃) δ: −0.07 (s, 9H), 0.88-0.96 (m, 5H), 1.82-1.98 (m, 1H),2.10-2.29 (m, 1H), 2.55-2.70 (m, 1H), 3.08-3.21 (m, 1H), 3.42-3.64 (m,4H), 3.70-3.82 (m, 1H), 5.40-5.50 (m, 1H), 5.80 (s, 2H), 6.40 (d, J =7.8 Hz, 1H), 6.68 (d, J = 3.9 Hz, 1H), 7.46 (d, J = 3.9 Hz, 1H), 7.60(d, J = 7.8 Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H),8.06 (d, J = 7.8 Hz, 1H), 8.12 (s, 1H), 9.41 (s, 1H). LC/MS: condition3, retention time = 2.59 min LC/MS (ESI⁺) m/z; 578 [M + H]⁺ 63 ¹H-NMR(CDCl₃) δ: −0.07 (s, 9H), 0.82-0.99 (m, 2H), 1.03 (d, J = 6.9 Hz, 3H),1.26 (t, J = 7.2 Hz, 3H), 1.70-1.85 (m, 1H), 2.65-2.80 (m, 1H),3.24-3.42 (m, 1H), 3.57 (t, J = 8.4 Hz, 2H), 3.66-3.84 (m, 1H),3.90-4.02 (m, 1H), 4.10-4.29 (m, 4H), 5.12-5.22 (m, 1H), 5.76-5.84 (m,2H), 6.40 (d, J = 7.8 Hz, 1H), 6.72 (d, J = 3.9 Hz, 1H), 7.44 (d, J =3.9 Hz, 1H), 7.54 (d, J = 3.9 Hz, 1H), 9.43 (s, 1H). LC/MS: condition 1,retention time = 4.27 min LC/MS (ESI⁺) m/z; 485 [M + H]⁺ LC/MS (ESI⁻)m/z; 529 [M + HCOO]⁻ 64 ¹H-NMR (CDCl₃) δ: −0.08 (s, 9H), 0.92 (t, J =8.4 Hz, 2H), 1.04 (d, J = 6.9 Hz, 3H), 1.80-1.95 (m, 1H), 2.08-2.25 (m,1H), 2.70-2.88 (m, 1H), 3.42-3.60 (m, 1H), 3.56 (t, J = 8.4 Hz, 2H),3.65-3.82 (m, 2H), 4.32-4.46 (m, 1H), 5.21-5.38 (m, 1H), 5.78 (s, 2H),6.38 (d, J = 7.8 Hz, 1H), 6.72 (d, J = 4.2 Hz, 1H), 6.95-7.10 (m, 1H),7.20 (t, J = 8.1 Hz, 1H), 7.44 (d, J = 3.6 Hz, 1H), 7.45-7.60 (m, 3H),7.99 (d, J = 8.1 Hz, 1H), 9.38 (s, 1H). LC/MS: condition 3, retentiontime = 2.60 min LC/MS (ESI⁺) m/z; 600 [M + H]⁺ LC/MS (ESI⁻) m/z; 598 [M− H]⁻

TABLE^(b) 52 Rf Data 65 ¹H-NMR (CDCl₃) δ: −0.09 (s, 9H), 0.80-0.92 (m,2H), 0.95 (d, J = 7.2 Hz, 3H), 1.70-1.84 (m, 1H), 2.06-2.22 (m, 1H),2.60-2.73 (m, 1H), 3.11-3.28 (m, 1H), 3.37-3.59 (m, 2H), 3.78-3.91 (m,1H), 4.27-4.41 (m, 1H), 4.50-4.63 (m, 1H), 5.09-5.20 (m, 1H), 5.47 (d, J= 10.8 Hz, 1H), 5.63 (d, J = 10.2 Hz, 1H), 6.04 (d, J = 7.8 Hz, 1H),6.67 (d, J = 3.9 Hz, 1H), 7.17-7.40 (m, 3H), 7.41 (d, J = 3.6 Hz, 1H),7.78 (d, J = 8.7 Hz, 1H), 8.07 (s, 1H), 8.74 (s, 1H), 9.66 (br s, 1H).LC/MS: condition 3, retention time = 2.74 min LC/MS (ESI⁺) m/z; 600 [M +H]⁺ LC/MS (ESI⁻) m/z; 598 [M − H]⁻ 66 LC/MS: condition 3, retention time= 2.62 min LC/MS (ESI⁺) m/z; 585 [M + H]⁺ 67 LC/MS: condition 3,retention time = 2.68 min LC/MS (ESI⁺) m/z; 585 [M + H]⁺ 68 LC/MS:condition 3, retention time = 2.51 min LC/MS (ESI⁺) m/z; 549 [M + H]⁺ 69¹H-NMR (CDCl₃) δ: −0.06 (s, 9H), 0.82-0.99 (m, 5H), 1.80-1.96 (m, 1H),2.09-2.28 (m, 1H), 2.51-2.68 (m, 1H), 3.07-3.26 (m, 1H), 3.42-3.63 (m,4H), 3.70-3.81 (m, 1H), 5.39-5.48 (m, 1H), 5.80 (dd, 10.5, 12.9 Hz, 2H),6.39 (d, J = 7.8 Hz, 1H), 6.67 (d, J = 3.9 Hz, 1H), 7.45 (d, J = 4.2 Hz,1H), 7.63 (d, J = 8.1 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.95 (d, J =8.1 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 8.09 (s, 1H), 9.42 (s, 1H).LC/MS: condition 3, retention time = 2.82 min LC/MS (ESI⁺) m/z; 621 [M +H]⁺ 70 LC/MS: condition 1, retention time = 2.69 min LC/MS (ESI⁺) m/z;585 [M + H]⁺ LC/MS (ESI⁻) m/z; 629 [M + HCOO]⁻ 71 LC/MS: condition 3,retention time = 2.72 min LC/MS (ESI⁺) m/z; 547 [M + H]⁺ 72 LC/MS:condition 1, retention time = 2.88 min LC/MS (ESI⁺) m/z; 222 [M + H]⁺ 73LC/MS: condition 1, retention time = 3.86 min LC/MS (ESI⁺) m/z; 540 [M +H]⁺ LC/MS (ESI⁻) m/z; 538 [M − H]⁻ 74 LC/MS: condition 1, retention time= 3.52 min LC/MS (ESI⁺) m/z; 235 [M + H]⁺ LC/MS (ESI⁻) m/z; 233 [M − H]⁻75 LC/MS: condition 1, retention time = 3.97 min LC/MS (ESI⁺) m/z; 553[M + H]⁺ LC/MS (ESI⁻) m/z; 551 [M − H]⁻ 76 LC/MS: condition 1, retentiontime = 4.34 min LC/MS (ESI⁺) m/z; 509 [M + H]⁺ LC/MS (ESI⁻) m/z; 553[M + HCOO]⁻ 77 LC/MS: condition 1, retention time = 1.26 min LC/MS(ESI⁺) m/z; 571 [M + H]⁺

TABLE^(b) 53 Rf Data 78 LC/MS: condition 1, retention time = 4.21 minLC/MS (ESI⁺) m/z; 571 [M + H]⁺ LC/MS (ESI⁻) m/z; 615 [M + HCOO]⁻ 79LC/MS: condition 1, retention time = 4.85 min LC/MS (ESI⁺) m/z; 571 [M +H]⁺ 80 LC/MS: condition 1, retention time = 3.89 min LC/MS (ESI⁺) m/z;528 [M + H]⁺ LC/MS (ESI⁻) m/z; 572 [M + HCOO]⁻ 81 LC/MS: condition 1,retention time = 4.45 min LC/MS (ESI⁺) m/z; 528 [M + H]⁺ 82 LC/MS:condition 1, retention time = 3.89 min LC/MS (ESI⁺) m/z; 528 [M + H]⁺ 83¹H-NMR (CDCl₃) δ: −0.15 (s, 9H), 0.93 (t, J = 8.1 Hz, 2H), 1.01 (d, J =7.2 Hz, 3H), 1.44 (s, 9H), 1.70-1.80 (m, 1H), 1.95-2.10 (m, 1H),2.60-2.77 (m, 1H), 3.25-3.45 (m, 1H), 3.57 (t, J = 8.1 Hz, 2H),3.64-3.90 (m, 2H), 4.00-4.20 (m, 1H), 5.10-5.22 (m, 1H), 5.80 (dd, J =10.8, 13.2 Hz, 2H), 6.48 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 3.6 Hz, 1H),7.44 (d, J = 4.2 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 9.43 (s, 1H). LC/MS:condition 1, retention time = 4.55 min LC/MS (ESI⁺) m/z; 513 [M + H]⁺LC/MS (ESI⁻) m/z; 557 [M + HCOO]⁻ 84 ¹H-NMR (CDCl₃) δ: −0.04 (s, 9H),0.87-1.08 (m, 5H), 1.71-2.10 (m, 2H), 2.40-3.30 (m, 8H), 3.58-3.72 (m,2H), 5.40-5.54 (m, 1H), 5.80-5.94 (m, 2H), 6.37 (d, J = 7.8 Hz, 1H),6.87 (d, J = 3.9 Hz, 1H), 6.99-7.15 (m, 2H), 7.15-7.30 (m, 2H),7.30-7.45 (m, 1H), 7.49 (d, J = 3.6 Hz, 1H), 8.44 (br s, 1H), 9.50 (s,1H). LC/MS: condition 3, retention time = 2.14 min LC/MS (ESI⁺) m/z; 535[M + H]⁺ 85 LC/MS: condition 3, retention time = 1.89 min LC/MS (ESI⁺)m/z; 481 [M + H]⁺ 86a LC/MS: condition 3, retention time = 3.17 minLC/MS (ESI⁺) m/z; 579 [M + H]⁺ 86b LC/MS: condition 3, retention time =3.09 min LC/MS (ESI⁺) m/z; 579 [M + H]⁺ 87 LC/MS: condition 3, retentiontime = 2.66 min LC/MS (ESI⁺) m/z; 327, 329 [M + H]⁺ LC/MS (ESI⁻) m/z;325, 327 [M − H]⁻ 88 ¹H-NMR (CDCl₃) δ: −0.06 (s, 9H), 0.91 (t, J = 8.4Hz, 2H), 3.53 (t, J = 8.4 Hz, 2H), 5.68 (s, 2H), 6.71 (d, J = 3.6 Hz,1H), 7.45 (d, J = 3.9 Hz, 1H), 8.81 (s, 1H). LC/MS: condition 3,retention time = 2.40 min LC/MS (ESI⁺) m/z; 326, 328 [M + H]⁺

TABLE^(b) 54 Rf Data 89 ¹H-NMR (CDCl₃) δ: −0.06 (s, 9H), 0.90 (t, J =7.5 Hz, 2H), 1.60-1.84 (m, 2H), 2.07-2.19 (m, 2H), 2.21-2.38 (m, 2H),2.77-2.91 (m, 2H), 3.46 (m, 4H), 3.92-4.10 (m, 1H), 5.57 (s, 4H), 6.58(d, J = 3.6 Hz, 1H), 7.08 (d, J = 3.9 Hz, 1H), 7.20-7.38 (m, 5H), 8.30(s, 1H), 9.39 (d, J = 7.5 Hz, 1H). LC/MS: condition 3, retention time =1.89 min LC/MS (ESI⁺) m/z; 480 [M + H]⁺ 90 ¹H-NMR (CDCl₃) δ: −0.05 (s,9H), 0.93 (t, J = 8.7 Hz, 2H), 1.80-1.96 (m, 2H), 2.10-2.28 (m, 1H),2.94-3.22 (m, 4H), 3.56 (t, J = 8.7 Hz, 2H), 3.59 (s, 2H), 4.68-4.85 (m,1H), 5.73 (s, 2H), 6.74 (d, J = 3.3 Hz, 1H), 7.22-7.48 (m, 6H), 8.03 (s,1H), 9.04 (s, 1H). LC/MS: condition 3, retention time = 2.18 min LC/MS(ESI⁺) m/z; 506 [M + H]⁺ 91 LC/MS: condition 3, retention time = 1.90min LC/MS (ESI⁺) m/z; 416 [M + H]⁺ 92 ¹H-NMR (CDCl₃) δ: −0.04 (s, 9H),0.94 (t, J = 8.1 Hz, 2H), 1.84-1.98 (m, 2H), 2.18-2.32 (m, 2H),3.00-3.18 (m, 4H), 3.57 (t, J = 8.1 Hz, 2H), 3.65 (s, 2H), 4.70-4.84 (m,1H), 5.75 (s, 2H), 6.73 (d, J = 3.6 Hz, 1H), 7.45 (d, J = 3.9 Hz, 1H),7.53 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.1 Hz, 2H), 8.09 (s, 1H), 9.06(s, 1H). LC/MS: condition 3, retention time = 2.23 min LC/MS (ESI⁺) m/z;531 [M + H]⁺ 93 ¹H-NMR (CDCl₃) δ: −0.05 (s, 9H), 0.93 (t, J = 7.5 Hz,2H), 1.81-1.96 (m, 2H), 2.18-2.30 (m, 2H), 2.93-3.26 (m, 4H), 3.51-3.62(m, 2H), 3.71 (s, 2H), 4.66-4.83 (m, 1H), 5.74 (s, 2H), 6.66-6.80 (m,2H), 7.44 (d, J = 4.2 Hz, 1H), 8.03 (br s, 1H), 9.05 (s, 1H). LC/MS:condition 3, retention time = 2.21 min LC/MS (ESI⁺) m/z; 546, 548 [M +H]⁺ 94 ¹H-NMR (CDCl₃) δ: −0.05 (s, 9H), 0.93 (t, J = 8.1 Hz, 2H),1.80-1.96 (m, 2H), 2.13-2.30 (m, 2H), 2.95-3.16 (m, 4H), 3.56 (t, J =8.1 Hz, 2H), 3.64 (s, 2H), 4.70-4.82 (m, 1H), 5.74 (s, 2H), 6.73 (d, J =3.9 Hz, 1H), 7.40-7.68 (m, 5H), 8.14 (s, 1H), 9.05 (s, 1H). LC/MS:condition 3, retention time = 2.43 min LC/MS (ESI⁺) m/z; 574 [M + H]⁺ 95LC/MS: condition 3, retention time = 2.87 min LC/MS (ESI⁺) m/z; 415 [M +H]⁺ 96 ¹H-NMR (CDCl₃) δ: −0.06 (s, 9H), 0.88 (t, J = 8.1 Hz, 2H), 2.76(s, 3H), 3.48-3.62 (m, 2H), 5.67 (s, 2H), 6.74 (d, J = 3.3 Hz, 1H), 7.43(d, J = 3.9 Hz, 1H), 8.72 (s, 1H). 97 LC/MS: condition 1, retention time= 3.32 min LC/MS (ESI⁺) m/z; 479 [M + H]⁺ 98 LC/MS: condition 1,retention time = 3.18 min LC/MS (ESI⁺) m/z; 489 [M + H]⁺ 99 LC/MS:condition 1, retention time = 2.88 min LC/MS (ESI⁺) m/z; 399 [M + H]⁺

TABLE^(b) 55 Rf Data 100 LC/MS: condition 1, retention time = 3.50 minLC/MS (ESI⁺) m/z; 529, 531 [M + H]⁺ 101 LC/MS: condition 1, retentiontime = 3.50 min LC/MS (ESI⁺) m/z; 557 [M + H]⁺ 102 LC/MS: condition 1,retention time = 3.26 min LC/MS (ESI⁺) m/z; 514 [M + H]⁺ 103 LC/MS:condition 1, retention time = 2.98 min LC/MS (ESI⁺) m/z; 532 [M + H]⁺104 LC/MS: condition 1, retention time = 0.35 min LC/MS (ESI⁺) m/z; 335[M + H]⁺ 105 LC/MS: condition 1, retention time = 3.30 min LC/MS (ESI⁺)m/z; 465 [M + H]⁺ 106 ¹H-NMR (CDCl₃) δ: −0.07 (s, 9H), 0.85-0.98 (m,2H), 1.52-1.79 (m, 2H), 2.04-2.38 (m, 4H), 2.79-2.95 (m, 2H), 3.44-3.62(m, 4H), 3.89-4.06 (m, 1H), 4.70 (s, 2H), 5.58 (s, 2H), 6.49 (d, J = 3.6Hz, 1H), 7.11 (d, J = 3.9 Hz, 1H), 7.23-7.40 (m, 5H), 7.82 (s, 1H). 107¹H-NMR (CD₃OD) δ: −0.03 (s, 9H), 0.92 (t, J = 8.0 Hz, 2H), 1.70-1.91 (m,2H), 2.12-2.51 (m, 4H), 2.90-3.10 (m, 2H), 3.54-3.78 (m, 4H), 3.96 (s,2H), 4.02-4.19 (m, 1H), 5.61 (s, 2H), 6.65 (d, J = 4.2 Hz, 1H), 7.28 (d,J = 3.6 Hz, 1H), 7.31-7.53 (m, 5H), 7.84 (s, 1H). LC/MS: condition 1,retention time = 0.37 min LC/MS (ESI⁺) m/z; 466 [M + H]⁺ 108 LC/MS:condition 1, retention time = 3.24 min LC/MS (ESI⁺) m/z; 492 [M + H]⁺109 LC/MS: condition 1, retention time = 2.96 min LC/MS (ESI⁺) m/z; 402[M + H]⁺ 110 LC/MS: condition 1, retention time = 4.45 min LC/MS (ESI⁺)m/z; 556 [M + H]⁺ 111 ¹H-NMR (CDCl₃) δ: −0.05 (s, 9H), 0.81-1.06 (m,2H), 1.55-2.05 (m, 3H), 2.05-2.29 (m, 1H), 2.93-3.20 (m, 4H), 3.46-3.70(m, 4H), 4.11-4.28 (m, 1H), 4.29-4.49 (m, 2H), 5.13 (s, 1H), 5.65 (s,2H), 6.47 (d, J = 3.6 Hz, 1H), 7.21-7.41 (m, 2H), 7.78 (d, J = 7.7 Hz,1H), 7.98 (s, 1H), 8.45-8.67 (m, 2H). LC/MS: condition 1, retention time= 2.92 min LC/MS (ESI⁺) m/z; 493 [M + H]⁺ 112 LC/MS: condition 1,retention time = 3.26 min LC/MS (ESI⁺) m/z; 517 [M + H]⁺ 113 LC/MS:condition 1, retention time = 3.48 min LC/MS (ESI⁺) m/z; 560 [M + H]⁺114 ¹H-NMR (CDCl₃) δ: −0.03 (s, 9H), 0.87-1.05 (m, 2H), 1.50-1.89 (m,4H), 2.02-2.28 (m, 2H), 2.92-3.25 (m, 2H), 3.60 (t, J = 8.3 Hz, 2H),4.30-3.72 (m, 3H), 5.70 (s, 2H), 6.44 (d, J = 3.6 Hz, 1H), 7.37 (d, J =3.9 Hz, 1H), 7.79 (s, 1H), 8.07 (s, 1H), 8.69 (s, 1H). LC/MS: condition1, retention time = 3.87 min LC/MS (ESI⁺) m/z; 529 [M + H]⁺

TABLE^(b) 56 Rf Data 115 ¹H-NMR (CDCl₃) δ: −0.05 (s, 9H), 0.80-1.03 (m,2H), 1.53-1.77 (m, 4H), 1.93-2.13 (m, 2H), 3.10-3.40 (m, 2H), 3.55 (t, J= 8.3 Hz, 2H), 3.90-4.07 (m, 1H), 4.31-4.53 (m, 2H), 4.82-4.98 (m, 1H),5.21 (s, 1H), 5.67 (s, 2H), 6.35-6.48 (m, 1H), 7.35 (d, J = 3.6 Hz, 1H),8.01 (s, 1H). LC/MS: condition 1, retention time = 4.17 min LC/MS (ESI⁺)m/z; 512 [M + H]⁺ 116 LC/MS: condition 1, retention time = 2.99 minLC/MS (ESI⁺) m/z; 499 [M + H]⁺ 117 LC/MS: condition 1, retention time =0.52 min LC/MS (ESI⁺) m/z; 349 [M + H]⁺ 118 LC/MS: condition 1,retention time = 3.57 min LC/MS (ESI⁺) m/z; 479 [M + H]⁺ 119 LC/MS:condition 1, retention time = 2.91 min LC/MS (ESI⁺) m/z; 481 [M + H]⁺120 LC/MS: condition 1, retention time = 3.42 min LC/MS (ESI⁺) m/z; 480[M + H]⁺ 121 LC/MS: condition 1, retention time = 3.36 min LC/MS (ESI⁺)m/z; 506 [M + H]⁺ 122 ¹H-NMR (CDCl₃) δ: 0.92-1.19 (m, 4H), 1.41-1.51 (m,1H), 1.74-1.96 (m, 4H), 2.55-2.68 (m, 1H), 3.45 (d, J = 6.3 Hz, 2H).LC/MS: condition 3, retention time = 0.29 min LC/MS (ESI⁺) m/z; 130 [M +H]⁺ 123 LC/MS: condition 3, retention time = 2.33 min LC/MS (ESI⁺) m/z;418 [M + H]⁺ 124 LC/MS: condition 3, retention time = 2.16 min LC/MS(ESI⁺) m/z; 428 [M + H]⁺ 125 LC/MS: condition 1, retention time = 3.62min LC/MS (ESI⁺) m/z; 230 [M + H]⁺ 126 LC/MS: condition 1, retentiontime = 0.39 min LC/MS (ESI⁺) m/z; 130 [M + H]⁺ 127 LC/MS: condition 1,retention time = 4.43 min LC/MS (ESI⁺) m/z; 418 [M + H]⁺ 128 LC/MS:condition 1, retention time = 4.08 min LC/MS (ESI⁺) m/z; 428 [M + H]⁺129 LC/MS: condition 1, retention time = 3.58 min LC/MS (ESI⁺) m/z; 547[M + H]⁺ 130 LC/MS: condition 1, retention time = 3.52 min LC/MS (ESI⁺)m/z; 524 [M + H]⁺ 131 LC/MS: condition 1, retention time = 3.38 minLC/MS (ESI⁺) m/z; 551 [M + H]⁺ 132 LC/MS: condition 1, retention time =3.34 min LC/MS (ESI⁺) m/z; 525 [M + H]⁺ 133 LC/MS: condition 1,retention time = 3.56 min LC/MS (ESI⁺) m/z; 557, 558, 559 [M + H]⁺

TABLE^(b) 57 Rf Data 134 LC/MS: condition 1, retention time = 3.46 minLC/MS (ESI⁺) m/z; 558 [M + H]⁺ 135 LC/MS: condition 1, retention time =3.44 min LC/MS (ESI⁺) m/z; 530, 532 [M + H]⁺ 136 LC/MS: condition 1,retention time = 3.56 min LC/MS (ESI⁺) m/z; 575 [M + H]⁺ 137 LC/MS:condition 1, retention time = 3.28 min LC/MS (ESI⁺) m/z; 540 [M + H]⁺138 LC/MS: condition 1, retention time = 3.30 min LC/MS (ESI⁺) m/z; 557,559 [M + H]⁺ 139 LC/MS: condition 1, retention time = 3.56 min LC/MS(ESI⁺) m/z; 573, 575 [M + H]⁺ 140 LC/MS: condition 1, retention time =3.50 min LC/MS (ESI⁺) m/z; 573, 575 [M + H]⁺ 141 LC/MS: condition 1,retention time = 3.44 min LC/MS (ESI⁺) m/z; 574, 576 [M + H]⁺ 142 LC/MS:condition 1, retention time = 3.46 min LC/MS (ESI⁺) m/z; 569 [M + H]⁺143 LC/MS: condition 1, retention time = 3.19 min LC/MS (ESI⁺) m/z; 528[M + H]⁺ 144 LC/MS: condition 1, retention time = 4.33 min LC/MS (ESI⁺)m/z; 543, 545 [M + H]⁺

TABLE^(b) 58 Rf Data 145 LC/MS: condition 3, retention time = 2.21 minLC/MS (ESI⁺) m/z; 559 [M + H]⁺ 146 LC/MS: condition 3, retention time =2.32 min LC/MS (ESI⁺) m/z; 590, 592 [M + H]⁺ 147 LC/MS: condition 3,retention time = 2.22 min LC/MS (ESI⁺) m/z; 544 [M + H]⁺ 148 LC/MS:condition 3, retention time = 2.05 min LC/MS (ESI⁺) m/z; 470 [M + H]⁺149 LC/MS: condition 3, retention time = 2.19 min LC/MS (ESI⁺) m/z; 486[M + H]⁺ 150 LC/MS: condition 3, retention time = 2.02 min LC/MS (ESI⁺)m/z; 528 [M + H]⁺ 151 ¹H-NMR (CDCl₃) δ: −0.04 (s, 9H), 0.91-0.97 (m,2H), 1.98 (d, J = 12.3 Hz, 2H), 2.59 (t, J = 11.7 Hz, 2H), 3.00-3.15 (m,4H), 3.54-3.59 (m, 2H), 3.66 (s, 2H), 4.73-4.81 (m, 1H), 5.75 (s, 2H),6.84 (d, J = 3.9 Hz, 1H), 7.48 (d, J = 3.6 Hz, 1H), 8.32 (br s, 1H),9.06 (s, 1H). LC/MS: condition 3, retention time = 2.35 min LC/MS (ESI⁺)m/z; 455 [M + H]⁺ 152 ¹H-NMR (CDCl₃) δ: −0.05 (s, 9H), 0.94 (t, J = 8.3Hz, 2H), 1.87 (d, J = 10.8 Hz, 2H), 2.67 (t, J = 12 Hz, 2H), 2.98-3.21(m, 6H), 3.56 (t, J = 8.3 Hz, 2H), 4.71-4.79 (m, 1H), 5.74 (s, 2H), 6.71(d, J = 3.9 Hz, 1H), 7.45 (d, J = 3.9 Hz, 1H), 8.08 (br s, 1H), 9.05 (s,1H). LC/MS: condition 3, retention time = 2.71 min LC/MS (ESI⁺) m/z; 498[M + H]⁺ 153 LC/MS: condition 3, retention time = 2.00 min LC/MS (ESI⁺)m/z; 497 [M + H]⁺ 154 LC/MS: condition 3, retention time = 2.33 minLC/MS (ESI⁺) m/z; 554 [M + H]⁺ 155 LC/MS: condition 3, retention time =1.99 min LC/MS (ESI⁺) m/z; 483 [M + H]⁺ 156 LC/MS: condition 3,retention time = 2.05 min LC/MS (ESI⁺) m/z; 500 [M + H]⁺ 157 ¹H-NMR(CDCl₃) δ: −0.04 (s, 9H), 0.93 (t, J = 8.4 Hz, 2H), 1.90 (d, J = 12.3Hz, 2H), 2.32 (t, J = 11.1 Hz, 2H), 2.57 (t, J = 7.1 Hz, 2H), 2.81 (t, J= 6.9 Hz, 2H), 3.01-3.17 (m, 4H), 3.56 (t, J = 8.3 Hz, 2H), 4.71-4.79(m, 1H), 5.74 (s, 2H), 6.72 (d, J = 3.9 Hz, 1H), 7.45 (d, J = 3.9 Hz,1H), 8.12 (br s, 1H), 9.05 (s, 1H). LC/MS: condition 3, retention time =1.97 min LC/MS (ESI⁺) m/z; 469 [M + H]⁺ 158 LC/MS: condition 1,retention time = 0.33 min LC/MS (ESI⁺) m/z; 168 [M + H]⁺

TABLE^(b) 59 Rf Data 159a ¹H-NMR (CDCl₃) δ: 1.52-1.80 (m, 9H), 2.05-2.25(m, 3H), 3.60-3.75 (m, 1H), 4.90-5.15 (m, 1H), 5.10 (s, 2H), 7.25-7.45(m, 5H). LC/MS: condition 1, retention time = 3.63 min LC/MS (ESI⁺) m/z;302 [M + H]⁺ 159b ¹H-NMR (CDCl₃) δ: 1.41-1.53 (m, 3H), 1.53-1.91 (m,7H), 2.01-2.25 (m, 3H), 3.73-3.86 (m, 1H), 4.98-5.02 (m, 1H), 5.10 (s,2H), 7.28-7.43 (m, 5H). LC/MS: condition 1, retention time = 3.63 minLC/MS (ESI⁺) m/z; 302 [M + H]⁺ 160 ¹H-NMR (DMSO-d₆) δ: 1.20 (d, J = 12.3Hz, 2H), 1.57 (m, 5H), 1.72 (s, 1H), 1.92-1.96 (m, 5H), 2.83 (s, 1H),4.26 (br s, 1H). LC/MS: condition 1, retention time = 0.33 min LC/MS(ESI⁺) m/z; 168 [M + H]⁺ 161 ¹H-NMR (DMSO-d₆) δ: 1.27 (d, J = 12.7 Hz,2H), 1.41-1.63 (m, 6H), 1.76-2.02 (m, 5H), 2.75-2.80 (br s, 1H). LC/MS:condition 1, retention time = 0.33 min LC/MS (ESI⁺) m/z; 168 [M + H]⁺162 ¹H-NMR (CDCl₃) δ: 1.48 (s, 9H), 4.70 (s, 4H). 163 ¹H-NMR (CDCl₃) δ:1.46 (s, 9H), 4.58-4.65 (m, 2H), 4.68-4.74 (m, 2H), 5.36-5.41 (m, 1H).LC/MS: condition 1, retention time = 3.44 min LC/MS (ESI⁺) m/z; 195 [M +H]⁺ 164 ¹H-NMR (CDCl₃) δ: 1.44 (s, 9H), 2.64 (d, J = 7.2 Hz, 2H),2.79-2.94 (m, 1H), 3.69 (dd, J = 8.8, 5.5 Hz, 2H), 4.13 (dd, J = 8.8,8.3 Hz, 2H). LC/MS: condition 1, retention time = 3.20 min LC/MS (ESI⁺)m/z; 197 [M + H]⁺ 165 LC/MS: condition 1, retention time = 0.33 minLC/MS (ESI⁺) m/z; 97 [M + H]⁺ 166 ¹H-NMR (CDCl₃) δ: −0.05 (s, 9H), 0.95(t, J = 8.4 Hz, 2H), 1.23 (m, 2H), 1.47 (m, 3H), 2.00 (d, J = 8.7 Hz,2H), 2.33 (d, J = 8.7 Hz, 2H), 3.58 (m, 4H), 5.63 (br s, 4H), 6.62 (d, J= 4.0 Hz, 1H), 7.13 (d, J = 4.0 Hz, 1H), 8.33 (s, 1H), 9.29 (d, J = 7.8Hz, 1H). LC/MS: condition 3, retention time = 1.99 min LC/MS (ESI⁺) m/z;419 [M + H]⁺ 167 ¹H-NMR (CDCl₃) δ: −0.04 (s, 9H), 0.97 (t, J = 8.4 Hz,2H), 1.28 (m, 2H), 1.43 (m, 1H), 1.74 (m, 1H), 2.09 (m, 4H), 2.80 (m,2H), 3.60 (t, J = 8.4 Hz, 2H), 3.60 (m, 2H), 4.75 (m, 1H), 5.78 (s, 2H),6.74 (d, J = 4.0 Hz, 1H), 7.47 (d, J = 4.0 Hz, 1H), 8.41 (s, 1H), 9.10(s, 1H). LC/MS: condition 3, retention time = 2.33 min LC/MS (ESI⁺) m/z;445 [M + H]⁺

TABLE^(b) 60 Rf Data 168 ¹H-NMR (CDCl₃) δ: −0.04 (s, 9H), 0.95 (t, J =8.1 Hz, 2H), 1.53 (m, 2H), 2.06 (m, 4H), 2.42 (m, 1H), 2.85 (m, 2H),3.60 (t, J = 8.1 Hz, 2H), 4.75 (m, 1H), 5.78 (br s, 2H), 6.70 (d, J =4.0 Hz, 1H), 7.79 (d, J = 4.0 Hz, 1H), 8.67 (br s, 1H), 9.10 (s, 1H),9.79 (s, 1H). LC/MS: condition 3, retention time = 2.52 min LC/MS (ESI⁺)m/z; 443 [M + H]⁺ 169 ¹H-NMR (CDCl₃) δ: −0.06 (s, 9H), 0.96 (t, J = 8.1Hz, 2H), 1.19 (m, 2H), 1.30 (br s, 1H), 1.67 (br s, 1H), 2.07 (m, 4H),2.08 (m, 2H), 2.80 (m, 2H), 3.25 (m, 2H), 3.60 (t, J = 8.1 Hz, 2H), 4.74(m, 1H), 5.78 (br s, 2H), 6.73 (d, J = 4.0 Hz, 1H), 7.47 (d, J = 4.0 Hz,1H), 9.10 (s, 1H). LC/MS: condition 3, retention time = 2.27 min LC/MS(ESI⁺) m/z; 526 [M + H]⁺ 170 ¹H-NMR (CDCl₃) δ: −0.06 (s, 9H), 0.92 (t, J= 8.1 Hz, 2H), 1.88 (m, 2H), 2.03 (m, 4H), 2.37 (m, 1H), 2.85 (m, 2H),3.53 (t, J = 8.1 Hz, 2H), 4.70 (m, 1H), 5.34 (m, 1H), 5.72 (br s, 2H),6.30-6.74 (m, 1H), 6.70 (d, J = 4.0 Hz, 1H), 7.44 (d, J = 4.0 Hz, 1H),9.04 (s, 1H), 9.31 (s, 1H). LC/MS: condition 3, retention time = 2.65min LC/MS (ESI⁺) m/z; 446 [M + H]⁺ 171 LC/MS: condition 3, retentiontime = 2.23 min LC/MS (ESI⁺) m/z; 457 [M + H]⁺ 172 LC/MS: condition 3,retention time = 2.23 min LC/MS (ESI⁺) m/z; 457 [M + H]⁺ 173 LC/MS:condition 3, retention time = 2.46 min LC/MS (ESI⁺) m/z; 483 [M + H]⁺174 LC/MS: condition 3, retention time = 2.28 min LC/MS (ESI⁺) m/z; 483[M + H]⁺ 175 ¹H-NMR (CDCl₃) δ: −0.04 (s, 9H), 0.91 (t, J = 7.3 Hz, 2H),1.53-1.88 (m, 8H), 2.02-2.12 (m, 2H), 2.18-2.27 (m, 1H), 2.37-2.49 (m,2H), 2.63 (s, 3H), 3.54 (d, J = 7.3 Hz, 2H), 4.05-4.20 (m, 1H), 5.61 (s,2H), 6.53 (d, J = 3.6 Hz, 1H), 7.07 (d, J = 3.6 Hz, 1H), 8.67 (s, 1H),10.78 (d, J = 7.6 Hz, 1H). LC/MS: condition 1, retention time = 4.23 minLC/MS (ESI⁺) m/z; 456 [M + H]⁺ LC/MS (ESI⁻) m/z; 500 [M + HCOO]⁻ 176¹H-NMR (CDCl₃) δ: −0.05 (s, 9H), 0.91 (t, J = 8.3 Hz, 2H), 1.40-1.62 (m,4H), 1.73-2.13 (m, 6H), 2.18-2.28 (m, 1H), 2.30-2.42 (m, 2H), 2.65 (s,3H), 3.54 (d, J = 8.3 Hz, 2H), 4.19-4.30 (m, 1H), 5.58 (s, 2H), 6.51 (d,J = 4.0 Hz, 1H), 7.07 (d, J = 4.0 Hz, 1H), 8.66 (s, 1H), 10.75 (d, J =8.0 Hz, 1H). LC/MS: condition 1, retention time = 4.07 min LC/MS (ESI⁺)m/z; 456 [M + H]⁺ LC/MS (ESI⁻) m/z; 500 [M + HCOO]⁻

TABLE^(b) 61 Rf Data 177 LC/MS: condition 3, retention time = 2.33 minLC/MS (ESI⁺) m/z; 466 [M + H]⁺ 178 LC/MS: condition 3, retention time =2.15 min LC/MS (ESI⁺) m/z; 466 [M + H]⁺ 179 ¹H-NMR (CDCl₃) δ: 3.01 (d, J= 13.2 Hz, 1H), 3.62 (d, J = 13.2 Hz, 1H), 7.35 (m, 1H), 7.93 (m, 1H),8.60 (m, 1H), 8.78 (s, 1H). LC/MS: condition 3, retention time = 0.39min LC/MS (ESI⁺) m/z; 207 [M + H]⁺

TABLE^(b) 62 Ex Data 1 ¹H-NMR (CDCl₃) δ: 1.10-2.00 (m, 10H), 1.58 (d, J= 6.3 Hz, 3H), 3.90-4.10 (m, 1H), 4.67 (d, J = 10.2 Hz, 1H), 4.83 (d, J= 10.2 Hz, 1H), 5.13 (q, J = 6.6 Hz, 1H), 6.43 (.d, J = 3.6 Hz, 1H),7.17 (d, J = 3.3 Hz, 1H), 7.89 (s, 1H), 9.29 (br s, 1H). LC/MS:condition 1, retention time = 2.82 min LC/MS (ESI⁺) m/z; 272 [M + H]⁺ 2¹H-NMR (CDCl₃) δ: 1.10-1.90 (m, 8H), 1.95-2.10 (m, 2H), 3.95-4.10 (m,1H), 4.78 (s, 2H), 4.96 (s, 2H), 6.43 (d, J = 3.6 Hz, 1H), 7.17 (d, J =3.3 Hz, 1H), 7.81 (s, 1H), 9.45 (br s, 1H). LC/MS: condition 1,retention time = 2.37 min LC/MS (ESI⁺) m/z; 258 [M + H]⁺ 3 ¹H-NMR(CDCl₃) δ: 1.50-2.00 (m, 6H), 2.00-2.15 (m, 2H), 2.20-2.35 (m, 2H),4.90-5.05 (m, 1H), 6.46 (d, J = 7.8 Hz, 1H), 6.80-6.85 (m, 1H),7.40-7.50 (m, 1H), 7.80 (d, J = 8.1 Hz, 1H), 9.46 (s, 1H), 11.25 (br s,1H). LC/MS: condition 1, retention time = 3.32 min LC/MS (ESI⁺) m/z; 268[M + H]⁺ 4 LC/MS: condition 1, retention time = 0.79 min LC/MS (ESI⁺)m/z; 373 [M + H]⁺ 5 LC/MS: condition 1, retention time = 0.50 min LC/MS(ESI⁺) m/z; 283 [M + H]⁺ 6a ¹H-NMR (CDCl₃) δ: 0.87 (d, J = 7.2 Hz, 3H),1.60-2.00 (m, 2H), 2.40-2.60 (m, 2H), 2.75-3.00 (m, 2H), 3.00-3.20 (m,1H), 3.70 (s, 2H), 5.40-5.50 (m, 1H), 6.42 (d, J = 7.8 Hz, 1H),6.80-6.85 (m, 1H), 7.00-7.20 (m, 3H), 7.45-7.50 (m, 1H), 8.51 (br s,1H), 9.46 (s, 1H), 11.77 (br s, 1H). LC/MS: condition 1, retention time= 2.86 min LC/MS (ESI⁺) m/z; 409 [M + H]⁺ 6b ¹H-NMR (CDCl₃) δ: 0.88 (d,J = 7.2 Hz, 3H), 1.60-2.00 (m, 2H), 2.37 (s, 3H), 2.40-2.55 (m, 2H),2.55-2.70 (m, 1H), 2.80-2.90 (m, 1H), 2.95-3.05 (m, 1H), 5.40-5.50 (m,1H), 6.42 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 3.3 Hz, 1H), 7.40-7.50 (m,1H), 8.30-8.50 (m, 1H), 9.48 (s, 1H), 11.85 (br s, 1H). LC/MS: condition1, retention time = 0.50 min LC/MS (ESI⁺) m/z; 297 [M + H]⁺ 7 ¹H-NMR(CD₃OD) δ: 1.00-1.10 (m, 3H), 1.80-1.95 (m, 1H), 2.10-2.20 (m, 1H),2.70-2.90 (m, 1H), 3.20-3.30 (m, 1H), 3.35 (s, 2H), 3.60-3.75 (m, 1H),3.90-4.25 (m, 1H), 4.25-4.55 (m, 1H), 5.25-5.50 (m, 1H), 6.40-6.55 (m,1H), 6.85-7.00 (m, 1H), 7.50-7.60 (m, 1H), 8.00-8.10 (m, 1H), 9.21 (s,1H). LC/MS: condition 1, retention time = 1.92 min LC/MS (ESI⁺) m/z; 350[M + H]⁺ 8 LC/MS: condition 1, retention time = 3.09 min LC/MS (ESI⁺)m/z; 365 [M + H]⁺ LC/MS (ESI⁻) m/z; 363 [M − H]⁻

TABLE^(b) 63 Ex Data 9 ¹H-NMR (CD₃OD) δ: 1.01-1.08 (m, 3H), 1.77-1.91(m, 1H), 2.11-2.19 (m, 1H), 2.74-2.85 (m, 1H), 3.11-3.18 (m, 1H),3.59-3.82 (m, 3H), 4.00 (dd, J = 9.1, 12.7 Hz, 1H), 4.17 (d, J = 6.8 Hz,1H), 4.35-4.49 (m, 1H), 5.30-5.44 (m, 1H), 6.40-6.45 (m, 1H), 6.86-6.88(m, 1H), 7.53-7.55 (m, 1H), 8.00-8.05 (m, 1H), 9.21 (s, 1H). LC/MS:condition 2, retention time = 3.29 min LC/MS (ESI⁺) m/z; 393 [M + 1]⁺LC/MS (ESI⁻) m/z; 391 [M − 1]⁻ 10 ¹H-NMR (CDCl₃) δ: 1.02 (d, J = 7.5 Hz,3H), 1.15 (d, J = 7.2 Hz, 6H), 1.80-1.95 (m, 1H), 2.10-2.40 (m, 2H),2.70-2.80 (m, 1H), 2.91 (d, J = 6.3 Hz, 2H), 3.25-3.40 (m, 1H),3.50-3.70 (m, 1H), 3.70-3.80 (m, 1H), 3.85-4.00 (m, 1H), 5.40-5.55 (m,1H), 6.41 (d, J = 7.8 Hz, 1H), 6.70-6.80 (m, 1H), 7.40-7.50 (m, 1H),7.67 (d, J = 7.8 Hz, 1H), 9.39 (s, 1H), 11.91 (br s, 1H). LC/MS:condition 1, retention time = 3.44 min LC/MS (ESI⁺) m/z; 403 [M + H]⁺LC/MS (ESI⁻) m/z; 401 [M − H]⁻ 11 ¹H-NMR (CD₃OD) δ: 1.00 (d, J = 6.9 Hz,3H), 1.85-2.00 (m, 1H), 2.10-2.25 (m, 1H), 2.65-2.80 (m, 1H), 3.50-3.70(m, 2H), 3.90-4.10 (m, 2H), 4.31 (q, J = 9.6 Hz, 2H), 5.50-5.60 (m, 1H),6.43 (d, J = 8.1 Hz, 1H), 6.92 (d, J = 3.9 Hz, 1H), 7.57 (d, J = 3.6 Hz,1H), 8.15 (d, J = 8.1 Hz, 1H), 9.22 (s, 1H). LC/MS: condition 1,retention time = 3.37 min LC/MS (ESI⁺) m/z; 429 [M + H]⁺ LC/MS (ESI⁻)m/z; 427 [M − H]⁻ 12 LC/MS: condition 1, retention time = 3.51 min LC/MS(ESI⁺) m/z; 304 [M + H]⁺ LC/MS (ESI⁻) m/z; 302 [M − H]⁻ 13 LC/MS:condition 1, retention time = 2.94 min LC/MS (ESI⁺) m/z; 269 [M + H]⁺ 14¹H-NMR (CDCl₃) δ: 1.01 (d, J = 7.2 Hz, 3H), 1.53-1.92 (m, 4H), 2.09-2.38(m, 2H), 2.48-2.73 (m, 2H), 2.75-2.99 (m, 1H), 3.37-2.58 (m, 2H),4.45-4.62 (m, 1H), 4.88-5.01 (m, 2H), 6.41 (d, J = 3.6 Hz, 1H), 7.12 (d,J = 3.6 Hz, 1H), 7.30-7.35 (m, 5H), 7.75 (s, 1H), 9.40 (br s, 1H). 15LC/MS: condition 1, retention time = 0.50 min LC/MS (ESI⁺) m/z; 273 [M +H]⁺ 16 ¹H-NMR (CDCl₃) δ: 1.15-1.27 (m, 3H), 1.70-2.05 (m, 2H), 2.44-2.55(m, 1H), 3.48-3.94 (m, 5H), 4.32-4.36 (m, 1H), 4.65-4.85 (m, 2H),4.95-5.07 (m, 2H), 6.32-6.38 (m, 1H), 7.19-7.29 (m, 2H), 7.83-7.88 (m,1H), 9.60-9.49 (m, 1H). LC/MS: condition 1, retention time = 0.54 minLC/MS (ESI⁺) m/z; 340 [M + H]⁺ 17 LC/MS: condition 1, retention time =2.27 min LC/MS (ESI⁺) m/z; 271 [M + H]⁺ 18 LC/MS: condition 1, retentiontime = 3.27 min LC/MS (ESI⁺) m/z; 269 [M + H]⁺ 19 LC/MS: condition 1,retention time = 0.54 min LC/MS (ESI⁺) m/z; 255 [M + H]⁺

TABLE^(b) 64 Ex Data 20 ¹H-NMR (DMSO-d₆) δ: 1.20-2.10 (m, 10H), 6.25 (d,J = 8.0 Hz, 1H), 6.42-6.58 (m, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.49 (s,1H), 9.10 (s, 1H). LC/MS: condition 1, retention time = 3.24 min LC/MS(ESI⁺) m/z; 269 [M + 1]⁺ LC/MS (ESI⁻) m/z; 267 [M − 1]⁻

TABLE^(b) 65 Ex Data 21 ¹H-NMR (CDCl₃) δ: 0.23 (d, J = 6.9 Hz, 3H),1.42-1.56 (m, 1H), 1.60-1.80 (m, 1H), 1.86-2.01 (m, 1H), 2.08-2.21 (m,1H), 2.72-2.82 (m, 1H), 3.05-3.18 (m, 1H), 3.60 (s, 2H), 3.68 (d, J =11.4 Hz, 1H), 5.50-5.58 (m, 1H), 6.48 (d, J = 7.8 Hz, 1H), 7.25-7.42 (m,5H), 7.48 (s, 1H), 9.38 (s, 1H), 9.54 (d, J = 7.8 Hz, 1H). LC/MS:condition 1, retention time = 3.31 min LC/MS (ESI⁺) m/z; 451, 453 [M +H]⁺ 22 ¹H-NMR (CDCl₃) δ: 0.31 (d, J = 6.6 Hz, 3H), 1.40-1.55 (m, 1H),1.60-1.85 (m, 1H), 1.90-2.05 (m, 1H), 2.10-2.25 (m, 1H), 2.70-2.80 (m,1H), 3.05-3.20 (m, 1H), 3.50-3.65 (m, 1H), 3.59 (s, 2H), 5.45-5.50 (m,1H), 6.48 (d, J = 8.1 Hz, 1H), 7.25-7.50 (m, 6H), 9.39 (s, 1H), 9.49 (d,J = 8.4 Hz, 1H), 11.9 (br s, 1H). LC/MS: condition 1, retention time =3.09 min LC/MS (ESI⁺) m/z; 407, 409 [M + H]⁺ LC/MS (ESI⁻) m/z; 405, 407[M − H]⁻ 23 ¹H-NMR (CDCl₃) δ: 0.86 (d, J = 6.9 Hz, 3H), 1.60-1.80 (m,1H), 1.85-2.00 (m, 1H), 2.22 (s, 3H), 2.40-2.60 (m, 2H), 2.75-2.90 (m,2H), 3.00-3.10 (m, 1H), 3.65 (dd, J = 22.2, 9.6 Hz, 2H), 5.40-5.50 (m,1H), 6.80 (s, 1H), 7.20-7.50 (m, 6H), 8.58 (br s, 1H), 9.49 (s, 1H),11.93 (br s, 1H). LC/MS: condition 1, retention time = 1.00 min LC/MS(ESI⁺) m/z; 387 [M + H]⁺ LC/MS (ESI⁻) m/z; 385 [M − H]⁻ 24 LC/MS:condition 1, retention time = 2.74 min LC/MS (ESI⁺) m/z; 451, 453 [M +H]⁺ LC/MS (ESI⁻) m/z; 449, 451 [M − H]⁻ 25 ¹H-NMR (CD₃OD) δ: 0.95 (d, J= 7.2 Hz, 3H), 1.90-2.00 (m, 1H), 2.10-2.25 (m, 1H), 2.60-2.70 (m, 1H),3.50-3.60 (m, 2H), 3.85-4.05 (m, 2H), 5.45-5.60 (m, 1H), 6.40 (d, J =8.1 Hz, 1H), 6.82 (d, J = 3.9 Hz, 1H), 7.54 (d, J = 3.6 Hz, 1H),7.80-7.90 (m, 2H), 8.00-8.05 (m, 1H), 8.10-8.15 (m, 1H), 8.16 (d, J =7.8 Hz, 1H), 9.20 (s, 1H). LC/MS: condition 3, retention time = 1.73 minLC/MS (ESI⁺) m/z; 448 [M + H]⁺ LC/MS (ESI⁻) m/z; 446 [M − H]⁻ 26 LC/MS:condition 3, retention time = 1.78 min LC/MS (ESI⁺) m/z; 448 [M + H]⁺LC/MS (ESI) m/z; 446 [M − H] 27 ¹H-NMR (CDCl₃) δ: 1.04 (d, J = 6.9 Hz,3H), 1.26 (t, J = 6.9 Hz, 3H), 1.70-1.86 (m, 1H), 2.00-2.18 (m, 1H),2.68-2.84 (m, 1H), 3.28-3.50 (m, 1H), 3.68-3.88 (m, 1H), 3.88-4.02 (m,1H), 4.05-4.38 (m, 3H), 5.15-5.25 (m, 1H), 6.43 (d, J = 7.8 Hz, 1H),6.73 (br s, 1H), 7.32 (br s, 1H), 7.58 (d, J = 8.1 Hz, 1H), 9.47 (s,1H), 11.51 (br s, 1H). LC/MS: condition 3, retention time = 1.59 minLC/MS (ESI⁺) m/z; 355 [M + H]⁺

TABLE^(b) 66 Ex Data 28 ¹H-NMR (CDCl₃) δ: 0.98 (d, J = 6.9 Hz, 3H),1.77-1.88 (m, 1H), 2.16-2.31 (m, 1H), 2.68-2.82 (m, 1H), 3.26-3.42 (m,1H), 3.90-4.05 (m, 1H), 4.10-4.28 (m, 1H), 4.44-4.59 (m, 1H), 5.38-5.50(m, 1H), 6.18 (d, J = 7.8 Hz, 1H), 6.89 (br s, 1H), 7.31 (t, J = 7.5 Hz,1H), 7.49-7.62 (m, 3H), 7.66 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 7.8 Hz,1H), 8.54 (br s, 1H). LC/MS: condition 3, retention time = 1.78 minLC/MS (ESI⁺) m/z; 470 [M + H]⁺ LC/MS (ESI⁻) m/z; 468 [M − H]⁻ 29 LC/MS:condition 3, retention time = 1.98 min LC/MS (ESI⁺) m/z; 470 [M + H]⁺LC/MS (ESI⁻) m/z; 468 [M − H]⁻ 30 LC/MS: condition 3, retention time =1.78 min LC/MS (ESI⁺) m/z; 455 [M + H]⁺ LC/MS (ESI) m/z; 453 [M − H] 31¹H-NMR (CDCl₃) δ: 1.10 (d, J = 7.2 Hz, 3H), 1.75-1.90 (m, 1H), 2.00-2.20(m, 1H), 2.79-2.99 (m, 1H), 3.41-4.03 (m, 3H), 4.60-5.08 (m, 1H),5.20-5.40 (m, 1H), 6.45 (d, J = 7.8 Hz, 1H), 6.70 (s, 1H), 7.42-7.86 (m,6H), 9.46 (s, 1H), 12.14 (s, 1H). LC/MS: condition 3, retention time =1.87 min LC/MS (ESI⁺) m/z; 455 [M + H]⁺ LC/MS (ESI⁻) m/z; 453 [M − H]⁻32 LC/MS: condition 3, retention time = 1.66 min LC/MS (ESI⁺) m/z; 419[M + H]⁺ 33 ¹H-NMR (CDCl₃) δ: 0.90 (s, 3H), 1.81-1.98 (m, 1H), 2.10-2.26(m, 1H), 2.51-2.69 (m, 1H), 3.18-3.33 (m, 1H), 3.34-3.52 (m, 1H),3.52-3.69 (m, 1H), 3.69-3.81 (m, 1H), 5.40-5.52 (m, 1H), 6.42 (d, J =7.8 Hz, 1H), 6.67 (s, 1H), 7.46 (s, 1H), 7.65-7.86 (m, 2H), 7.95 (d, J =7.5 Hz, 1H), 8.05 (d, J = 7.2 Hz, 1H), 8.10 (s, 1H), 9.43 (s, 1H), 11.40(s, 1H). LC/MS: condition 3, retention time = 2.07 min LC/MS (ESI⁺) m/z;491 [M + H]⁺ LC/MS (ESI⁻) m/z; 489 [M − H]⁻ 34 LC/MS: condition 3,retention time = 1.89 min LC/MS (ESI⁺) m/z; 455 [M + H]⁺ LC/MS (ESI⁻)m/z; 453 [M − H]⁻ 35 LC/MS: condition 3, retention time = 1.88 min LC/MS(ESI⁺) m/z; 417 [M + H]⁺ 36 LC/MS: condition 1, retention time = 2.57min LC/MS (ESI⁺) m/z; 410 [M + H]⁺ LC/MS (ESI⁻) m/z; 408 [M − H]⁻ 37LC/MS: condition 1, retention time = 2.57 min LC/MS (ESI⁺) m/z; 423 [M +H]⁺ LC/MS (ESI⁻) m/z; 421 [M − H]⁻ 38 LC/MS: condition 1, retention time= 3.20 min LC/MS (ESI⁺) m/z; 379 [M + H]⁺ LC/MS (ESI⁻) m/z; 377 [M − H]⁻

TABLE^(b) 67 Ex Data 39 LC/MS: condition 1, retention time = 3.00 minLC/MS (ESI⁺) m/z; 441 [M + H]⁺ LC/MS (ESI⁻) m/z; 439 [M − H]⁻ 40 LC/MS:condition 1, retention time = 3.02 min LC/MS (ESI⁺) m/z; 441 [M + H]⁺LC/MS (ESI⁻) m/z; 439 [M − H]⁻ 41 LC/MS: condition 1, retention time =3.50 min LC/MS (ESI⁺) m/z; 441 [M + H]⁺ LC/MS (ESI⁻) m/z; 439 [M − H]⁻42 LC/MS: condition 1, retention time = 2.40 min LC/MS (ESI⁺) m/z; 398[M + H]⁺ LC/MS (ESI⁻) m/z; 396 [M − H]⁻ 43 LC/MS: condition 1, retentiontime = 3.07 min LC/MS (ESI⁺) m/z; 398 [M + H]⁺ LC/MS (ESI⁻) m/z; 396 [M− H]⁻ 44 LC/MS: condition 1, retention time = 1.67 min LC/MS (ESI⁺) m/z;398 [M + H]⁺ LC/MS (ESI⁻) m/z; 396 [M − H]⁻ 45 LC/MS: condition 3,retention time = 1.84 min LC/MS (ESI⁺) m/z; 383 [M + H]⁺ 46 LC/MS:condition 3, retention time = 1.34 min LC/MS (ESI⁺) m/z; 405 [M + H]⁺ 47¹H-NMR (CDCl₃) δ: 0.88 (d, J = 7.2 Hz, 3H), 1.33-2.08 (m, 10H),2.40-2.79 (m, 4H), 2.86-3.12 (m, 2H), 5.38-5.49 (m, 1H), 6.41 (d, J =8.4 Hz, 1H), 6.80-6.90 (m, 1H), 7.40-7.48 (m, 1H), 8.38 (br s, 1H), 9.48(s, 1H), 11.33 (s, 1H). LC/MS: condition 3, retention time = 1.06 minLC/MS (ESI⁺) m/z; 351 [M + H]⁺ 48a ¹H-NMR (CDCl₃) δ: 0.83 (s, 9H), 1.04(d, J = 6.6 Hz, 3H), 1.36-2.17 (m, 12H), 2.70-3.00 (m, 2H), 3.38-3.90(m, 2H), 4.55-4.85 (m, 1H), 5.10-5.30 (m, 1H), 6.41 (d, J = 7.8 Hz, 1H),6.52 (s, 1H), 7.46 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 9.46 (s, 1H),11.74 (br s, 1H). LC/MS: condition 3, retention time = 2.37 min LC/MS(ESI⁺) m/z; 449 [M + H]⁺ 48b LC/MS: condition 3, retention time = 2.28min LC/MS (ESI⁺) m/z; 449 [M + H]⁺ 49 LC/MS: condition 3, retention time= 1.22 min LC/MS (ESI⁺) m/z; 376 [M + H]⁺ LC/MS (ESI⁻) m/z; 374 [M − H]⁻50 ¹H-NMR (DMSO-d₆) δ: 1.79-1.90 (m, 2H), 2.12-2.28 (m, 2H), 2.70-2.90(m, 2H), 2.90-3.04 (m, 2H), 3.63 (s, 2H), 4.62-4.87 (m, 1H), 6.64 (d, J= 3.6 Hz, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 3.6 Hz, 1H), 7.82(d, J = 8.4 Hz, 2H), 8.74 (s, 1H). LC/MS: condition 3, retention time =1.37 min LC/MS (ESI⁺) m/z; 401 [M + H]⁺ LC/MS (ESI⁻) m/z; 399 [M − H]⁻

TABLE^(b) 68 Ex Data 51 ¹H-NMR (DMSO-d₆) δ: 1.77-1.93 (m, 2H), 2.08-2.30(m, 2H), 2.66-2.89 (m, 2H), 2.98-3.14 (m, 2H), 3.69 (s, 2H), 4.60-4.80(m, 1H), 6.60-6.70 (m, 1H), 6.86 (d, J = 3.6 Hz, 1H), 6.96 (d, J = 3.3Hz, 1H), 7.61 (d, J = 3.0 Hz, 1H), 8.74 (s, 1H), 12.36 (br s, 1H).LC/MS: condition 3, retention time = 1.43 min LC/MS (ESI⁺) m/z; 416, 418[M + H]⁺ LC/MS (ESI⁻) m/z; 414, 416 [M − H]⁻ 52 ¹H-NMR (DMSO-d₆) δ:1.78-1.90 (m, 2H), 2.10-2.28 (m, 2H), 2.70-2.90 (m, 2H), 2.90-3.05 (m,2H), 3.63 (s, 2H), 4.61-4.79 (m, 1H), 6.65 (d, J = 3.3 Hz, 1H),7.52-7.64 (m, 3H), 7.71 (d, J = 8.1 Hz, 2H), 8.74 (s, 1H). LC/MS:condition 3, retention time = 1.75 min LC/MS (ESI⁺) m/z; 444 [M + H]⁺LC/MS (ESI⁻) m/z; 442 [M − H]⁻ 53 LC/MS: condition 3, retention time =1.79 min LC/MS (ESI⁺) m/z; 285 [M + H]⁺ 54 ¹H-NMR (CDCl₃) δ: 2.05-2.48(m, 6H), 3.10-3.30 (m, 2H), 3.64 (s, 2H), 4.91-5.10 (m, 1H), 6.46 (d, J= 8.3 Hz, 1H), 6.76-6.89 (m, 1H), 7.21-7.41 (m, 5H), 7.42-7.53 (m, 1H),7.82 (d, J = 8.0 Hz, 1H), 9.44 (s, 1H), 12.1 (s, 1H). LC/MS: condition1, retention time = 0.37 min LC/MS (ESI⁺) m/z; 359 [M + H]⁺ 55 ¹H-NMR(DMSO-d₆) δ: 1.98-2.22 (m, 4H), 2.30-2.68 (m, 2H), 3.00-3.18 (m, 2H),3.76 (s, 2H), 4.83-5.02 (m, 1H), 6.19 (d, J = 7.7 Hz, 1H), 6.80 (d, J =3.6 Hz, 1H), 6.90 (d, J = 3.6 Hz, 1H), 6.92-7.03 (m, 1H), 7.60 (d, J =3.3 Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H), 8.32 (s, 1H), 9.02 (s, 1H).LC/MS: condition 1, retention time = 0.94 min LC/MS (ESI⁺) m/z; 399 [M +H]⁺ 56 ¹H-NMR (CD₃OD) δ: 2.12-2.32 (m, 4H), 2.39-2.57 (m, 2H), 3.08-3.23(m, 2H), 3.75 (s, 2H), 5.09-5.25 (m, 1H), 6.47 (d, J = 8.04 Hz, 1H),6.95 (d, J = 4.2 Hz, 1H), 7.50-7.70 (m, 5H), 8.28 (d, J = 8.0 Hz, 1H),9.19 (s, 1H). LC/MS: condition 1, retention time = 1.65 min LC/MS (ESI⁺)m/z; 427 [M + H]⁺ 57 ¹H-NMR (DMSO-d₆) δ: 1.98-2.43 (m, 6H), 2.95-3.09(m, 2H), 3.69 (s, 2H), 4.86-5.01 (m, 1H), 6.19 (d, J = 8.0 Hz, 1H), 7.81(d, J = 3.9 Hz, 1H), 7.50-7.68 (m, 3H), 7.83 (d, J = 8.3 Hz, 2H), 8.21(d, J = 8.9 Hz, 1H), 9.02 (s, 1H). LC/MS: condition 1, retention time =0.37 min LC/MS (ESI⁺) m/z; 384 [M + H]⁺ 58 ¹H-NMR (DMSO-d₆) δ: 1.97-2.24(m, 4H), 2.35-2.60 (m, 2H), 2.92-3.11 (m, 2H), 3.73 (s, 2H), 4.85-5.03(m, 1H), 6.01 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 3.6 Hz, 1H), 6.60 (d, J= 3.6 Hz, 1H), 7.64-7.79 (m, 2H), 7.86 (d, J = 9.2 Hz, 1H), 8.20 (d, J =8.0 Hz, 1H), 8.32 (s, 1H). LC/MS: condition 1, retention time = 0.45 minLC/MS (ESI⁺) m/z; 402 [M + H]⁺

TABLE^(b) 69 Ex Data 59 ¹H-NMR (DMSO-d₆) δ: 1.74-1.90 (m, 2H), 1.98-2.19(m, 2H), 2.70-3.15 (m, 4H), 3.50 (s, 2H), 3.98-4.14 (m, 1H), 4.18 (s,2H), 6.31 (d, J = 3.0 Hz, 1H), 7.18 (br s, 1H), 7.22-7.29 (m, 1H),7.31-7.38 (m, 5H), 7.4 (br s, 1H), 7.93 (s, 1H). LC/MS: condition 1,retention time = 0.35 min LC/MS (ESI⁺) m/z; 362 [M + H]⁺ 60 ¹H-NMR(DMSO-d₆) δ: 1.80-1.98 (m, 2H), 2.68-3.00 (m, 4H), 3.63-3.60 (m, 2H),4.11-4.31 (m, 3H), 4.43 (s, 2H), 6.29 (br s, 1H), 7.27 (s, 1H),7.32-7.50 (m, 5H), 7.95 (s, 1H), 11.7 (s, 1H). LC/MS: condition 1,retention time = 2.78 min LC/MS (ESI⁺) m/z; 426 [M + H]⁺ 61 ¹H-NMR(DMSO-d₆) δ: 1.71-1.90 (m, 2H), 2.00-2.20 (m, 2H), 2.68-3.03 (m, 4H),3.54 (s, 2H), 3.98-4.26 (m, 3H), 6.31 (s, 1H), 7.19 (s, 1H), 7.32-7.49(m, 2H), 7.68-7.80 (m, 1H), 7.93 (s, 1H), 8.40-8.61 (m, 2H), 11.7 (s,1H). LC/MS: condition 1, retention time = 0.33 min LC/MS (ESI⁺) m/z; 363[M + H]⁺ 62 ¹H-NMR (DMSO-d₆) δ: 1.80-1.92 (m, 2H), 2.02-2.20 (m, 2H),2.68-3.09 (m, 4H), 3.60 (s, 2H), 4.00-4.29 (m, 3H), 6.31 (s, 1H), 7.21(s, 1H), 7.42 (s, 1H), 7.55 (d, J = 7.7 Hz, 2H), 7.81 (d, J = 7.4 Hz,2H), 7.94 (s, 1H), 11.7 (s, 1H). LC/MS: condition 1, retention time =0.35 min LC/MS (ESI⁺) m/z; 387 [M + H]⁺ 63 ¹H-NMR (DMSO-d₆) δ: 1.70-1.92(m, 2H), 2.01-2.20 (m, 2H), 2.71-3.12 (m, 4H), 3.60 (s, 2H), 4.00-4.33(m, 3H), 6.32 (d, J = 3.6 Hz, 1H), 7.21 (s, 1H), 7.42 (d, J = 3.6 Hz,1H), 7.58 (s, J = 7.7 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.94 (s, 1H),11.7 (s, 1H). LC/MS: condition 1, retention time = 0.64 min LC/MS (ESI⁺)m/z; 430 [M + H]⁺ 64 ¹H-NMR (DMSO-d₆) δ: 1.80-2.00 (m, 2H), 2.55-2.79(m, 2H), 2.85-3.10 (m, 2H), 4.20 (s, 2H), 4.25-4.51 (m, 3H), 6.39 (d, J= 2.4, 1H), 7.24 (s, 1H), 7.43 (s, 1H), 7.95 (s, 1H), 8.94 (s, 1H), 11.7(s, 1H). LC/MS: condition 1, retention time = 0.39 min LC/MS (ESI⁺) m/z;399 [M + H]⁺ 65 ¹H-NMR (CDCl₃) δ: 1.95-2.13 (m, 2H), 2.80-3.10 (m, 4H),3.48-3.62 (m, 2H), 4.02-4.18 (m, 1H), 4.40 (s, 2H), 4.80-4.98 (m, 1H),5.66 (s, 1H), 6.33-6.51 (m, 1H), 7.15-7.45 (m, 1H), 7.99 (s, 1H), 9.31(s, 1H). 66 ¹H-NMR (CDCl₃) δ: 1.89-2.00 (m, 2H), 2.11-2.28 (m, 2H),2.91-3.24 (m, 4H), 3.84 (s, 2H), 4.14-4.30 (m, 1H), 4.39 (s, 2H), 5.32(s, 1H), 6.45 (d, J = 3.9 Hz, 1H), 7.30 (d, J = 3.9 Hz, 1H), 7.73 (s,1H), 7.97 (s, 1H), 8.77 (s, 1H), 9.62 (s, 1H). LC/MS: condition 1,retention time = 0.33 min LC/MS (ESI⁺) m/z; 369 [M + H]⁺ 67 ¹H-NMR(CD₃OD) δ: 0.90-1.05 (m, 3H), 1.53-2.87 (m, 7H), 3.39-3.53 (m, 2H),4.20-4.56 (m, 3H), 6.48 (d, J = 2.4 Hz, 1H), 7.00-7.35 (m, 5H), 7.67 (s,1H), 7.90 (s, 1H).

TABLE^(b) 70 Ex Data 68 ¹H-NMR (CD₃OD) δ: 2.11-2.22 (m, 2H), 2.92-3.18(m, 4H), 3.41-3.52 (m, 2H), 4.33 (d, J = 3.9 Hz, 2H), 4.42-4.65 (m, 1H),6.44-6.49 (m, 1H), 7.36-7.43 (m, 1H), 7.92 (d, J = 4.5 Hz, 1H). LC/MS:condition 1, retention time = 0.35 min LC/MS (ESI⁺) m/z; 272 [M + H]⁺ 69LC/MS: condition 3, retention time = 1.22 min LC/MS (ESI⁺) m/z; 298 [M +H]⁺ 70 ¹H-NMR (CDCl₃) δ: 1.40-2.10 (m, 4H), 2.15-2.60 (m, 4H), 3.22-3.62(m, 4H), 4.88-5.21 (m, 1H), 6.45 (d, J = 7.7 Hz, 1H), 6.81 (s, 1H), 7.49(s, 1H), 7.74 (d, J = 7.7 Hz, 1H), 9.43 (s, 1H), 12.1 (s, 1H). LC/MS:condition 1, retention time = 2.62 min LC/MS (ESI⁺) m/z; 298 [M + H]⁺ 71¹H-NMR (CDCl₃) δ: 2.08-2.31 (m, 4H), 2.32-2.53 (m, 2H), 3.12-3.32 (m,2H), 3.73 (s, 2H), 4.90-5.11 (m 1H), 6.36 (d, J = 3.6 Hz, 1H), 6.46 (d,J = 8.3 Hz, 1H), 6.78 (d, J = 3.9 Hz, 2H), 7.47 (d, J = 3.9 Hz, 1H),7.79 (d, J = 8.3 Hz, 1H), 9.43 (s, 1H), 11.6 (s, 1H). LC/MS: condition1, retention time = 0.89 min LC/MS (ESI⁺) m/z; 417 [M + H]⁺ 72 LC/MS:condition 1, retention time = 0.55 min LC/MS (ESI⁺) m/z; 394 [M + H]⁺ 73LC/MS: condition 1, retention time = 0.62 min LC/MS (ESI⁺) m/z; 421 [M +H]⁺ 74 ¹H-NMR (CDCl₃) δ: 2.02-2.49 (m, 6H), 3.06-3.26 (m, 2H), 3.57 (d,J = 4.5 Hz, 2H), 4.83-5.13 (m, 1H), 5.87 (s, 1H), 6.43 (dd, J = 14.0,8.0 Hz, 1H), 6.76 (dd, J = 18.8, 3.3 Hz, 1H), 7.02-7.35 (m, 3H),7.42-7.56 (m, 1H), 7.79 (dd, J = 12.8, 8.0 Hz, 1H), 11.3 (s, 1H). LC/MS:condition 1, retention time = 0.40 min LC/MS (ESI⁺) m/z; 395 [M + H]⁺ 75¹H-NMR (DMSO-d₆) δ: 1.95-2.42 (m, 6H), 2.92-3.10 (m, 2H), 3.61 (s, 2H),4.86-5.04 (m, 1H), 6.19 (d, J = 7.7 Hz, 1H), 6.81 (d, J = 3.6 Hz, 1H),7.37 (d, J = 8.9 Hz, 1H), 7.52-7.68 (m, 3H), 8.22 (d, J = 8.3 Hz, 1H),9.02 (s, 1H). LC/MS: condition 1, retention time = 2.42 min LC/MS (ESI⁺)m/z; 427, 428, 429 [M + H]⁺ 76 LC/MS: condition 1, retention time = 0.87min LC/MS (ESI⁺) m/z; 428 [M + H]⁺ 77 ¹H-NMR (CDCl₃) δ: 1.79-2.60 (m,6H), 3.15-3.38 (m, 2H), 3.80 (s, 2H), 4.92-5.17 (m, 1H), 6.46 (d, J =8.3 Hz, 1H), 6.78 (d, J = 3.6 Hz, 1H), 7.41 (s, 1H), 7.49 (d, J = 3.3Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 9.39 (s, 1H), 12.2 (s, 1H). LC/MS:condition 1, retention time = 0.37 min LC/MS (ESI⁺) m/z; 400, 402 [M +H]⁺

TABLE^(b) 71 78 ¹H-NMR (DMSO-d₆) δ: 1.98-2.70 (m, 6H), 2.92-3.10 (m,2H), 3.67 (s, 2H), 4.84-5.03 (m, 1H), 6.18 (d, J = 7.7 Hz, 1H), 6.81 (d,J = 3.3 Hz, 1H), 7.43-7.62 (m, 2H), 7.75 (d, J = 6.9 Hz, 2H), 8.22 (d, J= 7.7 Hz, 1H), 9.02 (s, 1H). LC/MS: condition 1, retention time = 2.49min LC/MS (ESI⁺) m/z; 445 [M + H]⁺ 79 LC/MS: condition 1, retention time= 0.37 min LC/MS (ESI⁺) m/z; 410 [M + H]⁺ 80 ¹H-NMR (CDCl₃) δ: 2.09-2.56(m, 6H), 3.13-3.36 (m, 2H), 3.66 (s, 2H), 4.90-5.11 (m, 1H), 6.28 (dd, J= 9.5, 3.3 Hz, 2H), 6.40-6.55 (d, J = 8.3 Hz, 1H), 6.78 (d, J = 3.9 Hz,1H), 7.49 (d, J = 3.6 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 9.41 (s, 1H).LC/MS: condition 1, retention time = 0.62 min LC/MS (ESI⁺) m/z; 427, 429[M + H]⁺ 81 ¹H-NMR (CDCl₃) δ: 2.06-2.51 (m, 6H), 3.15-3.33 (m, 2H), 3.80(s, 2H), 4.90-5.11 (m, 1H), 6.47 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 3.9Hz, 1H), 6.89 (d, J = 0.9 Hz, 1H), 8.18 (d, J = 1.5 Hz, 1H), 7.47 (d, J= 3.9 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 9.44 (s, 1H). LC/MS: condition1, retention time = 0.87 min LC/MS (ESI⁺) m/z; 443, 445 [M + H]⁺ 82LC/MS: condition 1, retention time = 0.84 min LC/MS (ESI⁺) m/z; 443, 445[M + H]⁺ 83 ¹H-NMR (CDCl₃) δ: 2.05-2.52 (m, 6H), 3.18-3.30 (m, 2H), 3.82(s, 2H), 4.93-5.12 (m, 1H), 6.46 (d, J = 7.7 Hz, 1H), 6.78 (d, J = 3.9Hz, 1H), 7.44 (s, 1H), 7.48 (d, J = 3.9 Hz, 1H), 7.79 (d, J = 8.0 Hz,1H), 9.42 (s, 1H). LC/MS: condition 1, retention time = 0.50 min LC/MS(ESI⁺) m/z; 443, 445 [M + H]⁺ 84 ¹H-NMR (CDCl₃) δ: 2.05-2.43 (m, 6H),3.09-3.25 (m, 2H), 3.60 (s, 2H), 4.91-5.11 (m, 1H), 6.46 (d, J = 8.2 Hz,1H), 6.80 (d, J = 3.8 Hz, 1H), 6.95-7.11 (m, 2H), 7.15 (s, 1H), 7.46 (d,J = 3.4 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 9.43 (s, 1H). LC/MS:condition 1, retention time = 1.37 min LC/MS (ESI⁺) m/z; 439 [M + H]⁺ 85LC/MS: condition 1, retention time = 0.37 min LC/MS (ESI⁺) m/z; 398 [M +H]⁺ 86 LC/MS: condition 1, retention time = 0.35 min LC/MS (ESI⁺) m/z;380 [M + H]⁺ 87 LC/MS: condition 1, retention time = 3.32 min LC/MS(ESI⁺) m/z; 413, 415 [M + H]⁺ LC/MS (ESI⁻) m/z; 411, 413 [M − H]⁻

TABLE^(b) 72 88 LC/MS: condition 3, retention time = 0.37 min LC/MS(ESI⁺) m/z; 329 [M + H]⁺ LC/MS (ESI⁻) m/z; 327 [M − H]⁻ 89 LC/MS:condition 3, retention time = 1.43 min LC/MS (ESI⁺) m/z; 460, 462 [M +H]⁺ LC/MS (ESI⁻) m/z; 458, 460 [M − H]⁻ 90 LC/MS: condition 3, retentiontime = 1.33 min LC/MS (ESI⁺) m/z; 414 [M + H]⁺ 91 LC/MS: condition 3,retention time = 0.75 min LC/MS (ESI⁺) m/z; 340 [M + H]⁺ 92 LC/MS:condition 3, retention time = 1.22 min LC/MS (ESI⁺) m/z; 356 [M + H]⁺ 93LC/MS: condition 3, retention time = 1.03 min LC/MS (ESI⁺) m/z; 398 [M +H]⁺ 94 LC/MS: condition 3, retention time = 1.16 min LC/MS (ESI⁺) m/z;325 [M + H]⁺ 95 LC/MS: condition 3, retention time = 1.51 min LC/MS(ESI⁺) m/z; 368 [M + H]⁺ LC/MS (ESI⁻) m/z; 366 [M − H]⁻ 96 LC/MS:condition 3, retention time = 0.61 min LC/MS (ESI⁺) m/z; 367 [M + H]⁺ 97LC/MS: condition 3, retention time = 1.49 min LC/MS (ESI⁺) m/z; 424 [M +H]⁺ LC/MS (ESI⁻) m/z; 422 [M − H]⁻ 98 LC/MS: condition 3, retention time= 0.48 min LC/MS (ESI⁺) m/z; 353 [M + H]⁺ LC/MS (ESI) m/z; 351 [M − H]99 LC/MS: condition 3, retention time = 0.85 min LC/MS (ESI⁺) m/z; 370[M + H]⁺ 100 ¹H-NMR (DMSO-d₆) δ: 1.82 (d, J = 11.7 Hz, 2H), 2.18 (t, J =11.3 Hz, 2H), 2.61-2.78 (m, 6H), 3.05 (d, J = 11.4 Hz, 2H), 4.66 (t, J =11.7 Hz, 1H), 6.64 (d, J = 3.3 Hz, 1H), 7.60 (d, J = 3.3 Hz, 1H), 8.73(s, 1H), 11.48 (br s, 1H), 12.36 (br s, 1H). LC/MS: condition 3,retention time = 0.43 min LC/MS (ESI⁺) m/z; 339 [M + H]⁺ LC/MS (ESI⁻)m/z; 337 [M − H]⁻ 101 ¹H-NMR (DMSO-d₆) δ: 1.13 (m, 2H), 1.43 (br s, 1H),1.90 (m, 4H), 2.52 (m, 2H), 3.30 (m, 2H), 4.43 (t, J = 8.1 Hz, 1H), 4.62(m, 1H), 6.61 (d, J = 3.9 Hz, 1H), 7.60 (d, J = 3.9 Hz, 1H), 8.73 (s,1H), 11.42 (br s, 1H), 12.34 (br s, 1H). LC/MS: condition 3, retentiontime = 1.28 min LC/MS (ESI⁺) m/z; 315 [M + H]⁺ 102 ¹H-NMR (DMSO-d₆) δ:1.10 (m, 2H), 1.45 (br s, 1H), 1.93 (m, 4H), 2.31 (m, 1H), 3.23 (m, 6H),4.64 (m, 1H), 6.62 (d, J = 3.3 Hz, 1H), 7.60 (d, J = 3.3 Hz, 1H), 8.74(s, 1H), 11.42 (br s, 1H), 12.35 (br s, 1H). LC/MS: condition 3,retention time = 1.20 min LC/MS (ESI⁺) m/z; 396 [M + H]⁺

TABLE^(b) 73 103 ¹H-NMR (DMSO-d₆) δ: 1.23-1.60 (m, 2H), 1.81-1.92 (m,4H), 2.16 (br s, 1H), 2.60 (m, 2H), 4.66 (m, 1H), 5.64-5.77 (m, 1H),6.56-6.92 (m, 2H), 7.60 (d, J = 3.6 Hz, 1H), 8.73 (s, 1H). LC/MS:condition 3, retention time = 1.70 min LC/MS (ESI⁺) m/z; 336 [M + H]⁺104 LC/MS: condition 3, retention time = 1.45 min LC/MS (ESI⁺) m/z; 353[M + H]⁺ LC/MS (ESI⁻) m/z; 351 [M − H]⁻ 105 LC/MS: condition 3,retention time = 1.27 min LC/MS (ESI⁺) m/z; 353 [M + H]⁺ 106 ¹H-NMR(DMSO-d₆) δ: 1.43-1.84 (m, 7H), 2.00-2.23 (m, 4H), 2.63-2.77 (m, 2H),4.57 (br s, 1H), 4.91-4.98 (m, 1H), 6.21 (d, J = 8.3 Hz, 1H), 6.90 (d, J= 3.6 Hz, 1H), 7.58 (d, J = 3.6 Hz, 1H), 8.17 (d, J = 8.3 Hz, 1H), 9.05(s, 1H), 12.06 (br s, 1H). LC/MS: condition 3, retention time = 1.39 minLC/MS (ESI⁺) m/z; 336 [M + H]⁺ 107 ¹H-NMR (DMSO-d₆) δ: 1.40-1.54 (m,2H), 1.60-1.84 (m, 5H), 2.03-2.18 (m, 4H), 2.63 (br s, 2H), 4.65 (br s,1H), 5.06 (br s, 1H), 6.19 (d, J = 8.3 Hz, 1H), 6.85 (s, 1H), 7.57-7.63(m, 1H), 8.20 (d, J = 8.3 Hz, 1H), 9.03 (s, 1H), 12.26 (br s, 1H).LC/MS: condition 3, retention time = 1.24 min LC/MS (ESI⁺) m/z; 336 [M +H]⁺ 108 LC/MS: condition 3, retention time = 0.62 min LC/MS (ESI⁺) m/z;399 [M + H]⁺ 109 LC/MS: condition 3, retention time = 2.16 min LC/MS(ESI⁺) m/z; 512 [M + H]⁺ 110 LC/MS: condition 3, retention time = 0.74min LC/MS (ESI⁺) m/z; 383 [M + H]⁺ 111 LC/MS: condition 3, retentiontime = 0.47 min LC/MS (ESI⁺) m/z; 412 [M + H]⁺ 112 ¹H-NMR (DMSO-d₆) δ:1.07 (m, 2H), 1.51 (m, 2H), 1.96 (m, 5H), 2.27 (m, 3H), 2.40 (dd, J =13.5, 7.8 Hz, 1H), 2.50-2.57 (m, 3H), 2.68 (dd, J = 9.6, 6.3 Hz, 1H),4.17 (br s, 1H), 4.63, (d, J = 1.5 Hz, 2H), 6.62 (d, J = 4.0 Hz, 1H),7.59 (d, J = 4.0 Hz, 1H), 8.73 (s, 1H), 11.44 (br s, 1H), 12.34 (br s,1H). LC/MS: condition 3, retention time = 0.81 min LC/MS (ESI⁺) m/z; 384[M + H]⁺ 113 ¹H-NMR (DMSO-d₆) δ: 1.04 (m, 2H), 1.27 (br s, 1H), 1.86 (d,J = 8.7 Hz, 4H), 2.22 (d, J = 6.9 Hz, 2H), 2.50 (m, 2H), 2.62 (dd, J =7.5, 6.6 Hz, 2H), 3.48 (dd, J = 7.5, 6.3 Hz, 2H), 4.11 (br s, 1H), 4.58(m, 1H), 5.18 (br s, 1H), 6.57 (d, J = 3.3 Hz, 1H), 7.56 (d, J = 3.3 Hz,1H), 8.70 (s, 1H). LC/MS: condition 3, retention time = 0.74 min LC/MS(ESI⁺) m/z; 370 [M + H]⁺

TABLE^(b) 74 114 ¹H-NMR (DMSO-d₆) δ: 1.04 (m, 2H), 1.51 (br s, 1H), 1.90(m, 4H), 2.30 (d, J = 7.5 Hz, 2H), 2.50 (m, 2H), 2.86 (br s, 4H), 3.14(br s, 4H), 4.61 (m, 1H), 6.57 (d, J = 3.3 Hz, 1H), 7.56 (d, J = 3.3 Hz,1H), 8.71 (s, 1H), 11.40 (br s, 1H), 12.32 (br s, 1H). LC/MS: condition3, retention time = 1.17 min LC/MS (ESI⁺) m/z; 432 [M + H]⁺ 115 ¹H-NMR(DMSO-d₆) δ: 1.18 (m, 2H), 1.56 (br s, 1H), 1.93 (m, 8H), 2.21 (d, J =7.8 Hz, 2H), 2.50 (m, 6H), 4.64 (m, 1H), 6.62 (d, J = 3.9 Hz, 1H), 7.59(d, J = 3.9 Hz, 1H), 8.74 (d, J = 2.7 Hz, 1H), 11.39 (br s, 1H), 12.35(br s, 1H). LC/MS: condition 3, retention time = 1.19 min LC/MS (ESI⁺)m/z; 418 [M + H]⁺ 116 ¹H-NMR (DMSO-d₆) δ: 1.09 (m, 2H), 1.53 (br s, 1H),1.90 (d, J = 12.0 Hz, 2H), 2.01 (d, J = 12.0 Hz, 2H), 2.33 (d, J = 7.2Hz, 2H), 2.55 (m, 2H), 2.61 (m, 4H), 2.76 (m, 4H), 4.64 (m, 1H), 6.62(d, J = 3.6 Hz, 1H), 7.60 (d, J = 3.6 Hz, 1H), 8.75 (s, 1H), 11.33 (brs, 1H), 12.34 (br s, 1H). LC/MS: condition 3, retention time = 1.62 minLC/MS (ESI⁺) m/z; 420 [M + H]⁺ 117 ¹H-NMR (DMSO-d₆) δ: 0.09 (m, 2H),0.39 (m, 2H), 0.87 (m, 1H), 1.11 (m, 2H), 1.45 (br s, 1H), 1.92 (m, 4H),2.40 (d, J = 6.6 Hz, 2H), 2.43 (d, J = 6.6 Hz, 2H), 2.51 (m, 3H), 4.64(m, 1H), 6.61 (d, J = 3.9 Hz, 1H), 7.59 (d, J = 3.3 Hz, 1H), 8.73 (s,1H), 11.40 (br s, 1H), 12.32 (br s, 1H). LC/MS: condition 3, retentiontime = 1.23 min LC/MS (ESI⁺) m/z; 368 [M + H]⁺ 118 ¹H-NMR (DMSO-d₆) δ:1.09 (m, 2H), 1.52 (br s, 1H), 1.93 (m, 4H), 2.29 (m, 4H), 2.58-2.68 (m,7H), 4.64 (m, 1H), 6.61 (d, J = 3.6 Hz, 1H), 7.58 (d, J = 3.6 Hz, 1H),8.74 (s, 1H), 11.31 (br s, 1H), 12.32 (br s, 1H). LC/MS: condition 3,retention time = 0.97 min LC/MS (ESI⁺) m/z; 393 [M + H]⁺ 119 ¹H-NMR(DMSO-d₆) δ: 1.04 (m, 2H), 1.16 (s, 6H), 1.28 (br s, 1H), 1.89 (m, 4H),2.24 (d, J = 5.4 Hz, 2H), 2.51 (m, 2H), 2.84 (m, 4H), 4.61 (m, 1H), 6.59(d, J = 3.3 Hz, 1H), 7.59 (d, J = 3.3 Hz, 1H), 8.73 (s, 1H), 11.42 (brs, 1H), 12.34 (br s, 1H). LC/MS: condition 3, retention time = 1.23 minLC/MS (ESI⁺) m/z; 382 [M + H]⁺ 120 ¹H-NMR (DMSO-d₆) δ: 1.05 (m, 2H),1.51 (br s, 1H), 1.92 (m, 4H), 2.18 (m, 5H), 2.39 (t, J = 6.3 Hz, 2H),2.55 (m, 2H), 3.47 (dd, J = 12.0, 5.4 Hz, 2H), 4.28 (t, J = 5.4 Hz, 1H),4.64 (m, 1H), 6.62 (d, J = 3.6 Hz, 1H), 7.59 (d, J = 3.6 Hz, 1H), 8.73(s, 1H), 11.37 (br s, 1H), 12.34 (br s, 1H). LC/MS: condition 3,retention time = 0.75 min LC/MS (ESI⁺) m/z; 372 [M + H]⁺

TABLE^(b) 75 121 ¹H-NMR (DMSO-d₆) δ: 0.99 (m, 2H), 1.56 (br s, 1H), 1.89(d, J = 10.8 Hz, 2H), 2.00 (d, J = 10.8 Hz, 2H), 2.30 (d, J = 3.9 Hz,2H), 2.60 (m, 4H), 3.47 (dd, J = 12.0, 6.6 Hz, 2H), 3.59 (s, 2H), 4.31(t, J = 5.4 Hz, 1H), 4.61 (m, 1H), 6.58 (d, J = 3.6 Hz, 1H), 7.21-7.35(m, 5H), 7.57 (d, J = 3.6 Hz, 1H), 8.73 (s, 1H), 11.41 (br s, 1H), 12.33(br s, 1H). LC/MS: condition 3, retention time = 1.14 min LC/MS (ESI⁺)m/z; 448 [M + H]⁺ 122 ¹H-NMR (DMSO-d₆) δ: 0.85 (s, 2H), 0.92 (s, 2H),1.13 (m, 2H), 1.28 (br s, 1H), 1.90 (m, 4H), 2.26 (m, 1H), 2.56 (m, 4H),4.61 (m, 1H), 6.61 (d, J = 3.6 Hz, 1H), 7.59 (d, J = 3.6 Hz, 1H), 8.73(s, 1H), 11.45 (br s, 1H), 12.32 (br s, 1H). LC/MS: condition 3,retention time = 1.88 min LC/MS (ESI⁺) m/z; 422 [M + H]⁺ 123 ¹H-NMR(DMSO-d₆) δ: 1.09 (m, 2H), 1.46 (br s, 1H), 1.92 (m, 4H), 2.35-2.43 (m,9H), 2.60 (m, 4H), 3.56 (m, 4H), 4.63 (m, 1H), 6.61 (d, J = 3.6 Hz, 1H),7.59 (d, J = 3.6 Hz, 1H), 8.73 (s, 1H). LC/MS: condition 3, retentiontime = 1.40 min LC/MS (ESI⁺) m/z; 427 [M + H]⁺ 124 LC/MS: condition 3,retention time = 1.05 min LC/MS (ESI⁺) m/z; 393 [M + H]⁺ 125 ¹H-NMR(DMSO-d₆) δ: 0.04 (t, J = 4.2 Hz, 1H), 0.35 (dd, J = 7.2, 4.2 Hz, 1H),0.98 (s, 3H), 1.11 (s, 3H), 1.13 (m, 2H), 1.46 (br s, 1H), 1.82 (dd, J =7.2, 3.6 Hz, 1H), 1.93 (m, 5H), 2.41 (m, 2H), 2.55 (m, 2H), 4.64 (m,1H), 6.62 (d, J = 3.6 Hz, 1H), 7.59 (d, J = 3.6 Hz, 1H), 8.73 (s, 1H),11.37 (br s, 1H), 12.34 (br s, 1H). LC/MS: condition 3, retention time =1.37 min LC/MS (ESI⁺) m/z; 382 [M + H]⁺ 126 ¹H-NMR (DMSO-d₆) δ:1.05-1.27 (m, 3H), 1.36-1.58 (m, 6H), 1.94 (m, 4H), 2.41 (s, 1H), 2.42(d, J = 6.6 Hz, 2H), 2.55 (m, 6H), 3.93 (br s, 2H), 4.65 (m, 2H), 6.63(d, J = 3.6 Hz, 1H), 7.60 (d, J = 3.6 Hz, 1H), 8.73 (s, 1H). LC/MS:condition 3, retention time = 1.35 min LC/MS (ESI⁺) m/z; 426 [M + H]⁺127 ¹H-NMR (DMSO-d₆) δ: 1.16 (m, 2H), 1.48 (br s, 1H), 1.92 (m, 4H),2.55 (m, 5H), 3.61 (d, J = 6.0 Hz, 2H), 4.65 (m, 1H), 6.62 (d, J = 3.6Hz, 1H), 7.59 (d, J = 3.6 Hz, 1H), 8.73 (s, 1H), 11.34 (br s, 1H), 12.34(br s, 1H). LC/MS: condition 3, retention time = 1.02 min LC/MS (ESI⁺)m/z; 353 [M + H]⁺ 128 ¹H-NMR (DMSO-d₆) δ: 1.07 (m, 2H), 1.47 (m, 2H),1.56 (br s, 1H), 1.78 (d, J = 17.4 Hz, 2H), 1.95 (m, 6H), 2.15 (d, J =6.9 Hz, 2H), 2.21 (m, 1H), 2.55 (m, 2H), 2.92 (d, J = 17.4 Hz, 2H), 4.64(m, 1H), 6.62 (d, J = 3.6 Hz, 1H), 7.59 (d, J = 3.6 Hz, 1H), 8.73 (s,1H), 11.42 (br s, 1H), 12.34 (br s, 1H). LC/MS: condition 3, retentiontime = 1.36 min LC/MS (ESI⁺) m/z; 450 [M + H]⁺

TABLE^(b) 76 129 ¹H-NMR (DMSO-d₆) δ: 1.10 (m, 2H), 1.34 (br s, 1H), 1.89(m, 4H), 2.35 (d, J = 6.6 Hz, 2H), 2.55 (m, 2H), 3.11 (d, J = 8.4 Hz,2H), 3.53 (d, J = 8.4 Hz, 2H), 4.61 (m, 1H), 6.60 (d, J = 3.6 Hz, 1H),6.82 (s, 1H), 7.59 (d, J = 3.6 Hz, 1H), 8.70 (s, 1H), 11.37 (br s, 1H),12.34 (br s, 1H). LC/MS: condition 3, retention time = 1.20 min LC/MS(ESI⁺) m/z; 438 [M + H]⁺ LC/MS (ESI⁻) m/z; 436 [M − H]⁻ 130 ¹H-NMR(DMSO-d₆) δ: 1.09 (m, 2H), 1.51 (m, 2H), 1.74-1.84 (m, 4H), 1.92 (m,4H), 2.43 (d, J = 6.6 Hz, 2H), 2.55 (m, 4H), 3.59 (ddd, J = 14.4, 7.8,1.2 Hz, 1H), 3.72 (ddd, J = 14.4, 7.8, 1.2 Hz, 1H), 3.85 (m, 1H), 4.64(m, 1H), 6.62 (d, J = 3.6 Hz, 1H), 7.59 (d, J = 3.6 Hz, 1H), 8.73 (s,1H). LC/MS: condition 3, retention time = 1.21 min LC/MS (ESI⁺) m/z; 398[M + H]⁺ 131 LC/MS: condition 3, retention time = 1.10 min LC/MS (ESI⁺)m/z; 372 [M + H]⁺ 132 LC/MS: condition 3, retention time = 1.25 minLC/MS (ESI⁺) m/z; 503 [M + H]⁺ LC/MS (ESI⁻) m/z; 501 [M − H]⁻ 133 LC/MS:condition 3, retention time = 1.39 min LC/MS (ESI⁺) m/z; 313 [M + H]⁺134 ¹H-NMR (DMSO-d₆) δ: 1.19 (m, 2H), 1.42 (br s, 1H), 1.56 (dd, J =14.1, 7.5 Hz, 2H), 1.80 (m, 2H), 1.92 (m, 4H), 2.55 (m, 2H), 4.64 (m,1H), 6.62 (d, J = 3.6 Hz, 1H), 7.59 (d, J = 3.6 Hz, 1H), 8.73 (s, 1H).LC/MS: condition 3, retention time = 1.66 min LC/MS (ESI⁺) m/z; 338 [M +H]⁺ 135 LC/MS: condition 3, retention time = 1.80 min LC/MS (ESI⁺) m/z;463 [M + H]⁺ LC/MS (ESI) m/z; 461 [M − H] 136 LC/MS: condition 3,retention time = 1.85 min LC/MS (ESI⁺) m/z; 410 [M + H]⁺ LC/MS (ESI⁻)m/z; 408 [M − H]⁻ 137 LC/MS: condition 3, retention time = 2.13 minLC/MS (ESI⁺) m/z; 324 [M + H]⁺ LC/MS (ESI⁻) m/z; 322 [M − H]⁻ 138 LC/MS:condition 3, retention time = 2.13 min LC/MS (ESI⁺) m/z; 299 [M + H]⁺LC/MS (ESI⁻) m/z; 297 [M − H]⁻ 139 LC/MS: condition 3, retention time =2.49 min LC/MS (ESI⁺) m/z; 367 [M + H]⁺ LC/MS (ESI⁻) m/z; 365 [M − H]⁻140 LC/MS: condition 3, retention time = 1.86 min LC/MS (ESI⁺) m/z; 329[M + H]⁺ LC/MS (ESI⁻) m/z; 327 [M − H]⁻

TABLE^(b) 77 141 LC/MS: condition 3, retention time = 1.93 min LC/MS(ESI⁺) m/z; 343 [M + H]⁺ LC/MS (ESI⁻) m/z; 341 [M − H]⁻ 142 LC/MS:condition 3, retention time = 1.61 min LC/MS (ESI⁺) m/z; 398 [M + H]⁺LC/MS (ESI⁻) m/z; 396 [M − H]⁻ 143 LC/MS: condition 3, retention time =2.13 min LC/MS (ESI⁺) m/z; 329 [M + H]⁺ LC/MS (ESI⁻) m/z; 327 [M − H]⁻144 LC/MS: condition 3, retention time = 2.45 min LC/MS (ESI⁺) m/z; 359[M + H]⁺ LC/MS (ESI⁻) m/z; 357 [M − H]⁻ 145 LC/MS: condition 3,retention time = 2.19 min LC/MS (ESI⁺) m/z; 343 [M + H]⁺ LC/MS (ESI⁻)m/z; 341 [M − H]⁻ 146 LC/MS: condition 3, retention time = 2.26 minLC/MS (ESI⁺) m/z; 338 [M + H]⁺ LC/MS (ESI⁻) m/z; 336 [M − H]⁻ 147 LC/MS:condition 3, retention time = 2.41 min LC/MS (ESI⁺) m/z; 345 [M + H]⁺LC/MS (ESI⁻) m/z; 343 [M − H]⁻ 148 LC/MS: condition 3, retention time =2.83 min LC/MS (ESI⁺) m/z; 353 [M + H]⁺ LC/MS (ESI⁻) m/z; 351 [M − H]⁻149 LC/MS: condition 3, retention time = 2.58 min LC/MS (ESI⁺) m/z; 339[M + H]⁺ 150 LC/MS: condition 3, retention time = 2.31 min LC/MS (ESI⁺)m/z; 369 [M + H]⁺ LC/MS (ESI⁻) m/z; 367 [M − H]⁻ 151 LC/MS: condition 3,retention time = 1.95 min LC/MS (ESI⁺) m/z; 387 [M + H]⁺ LC/MS (ESI⁻)m/z; 385 [M − H]⁻ 152 LC/MS: condition 3, retention time = 1.94 minLC/MS (ESI⁺) m/z; 370 [M + H]⁺ 153 LC/MS: condition 3, retention time =1.62 min LC/MS (ESI⁺) m/z; 356 [M + H]⁺ LC/MS (ESI) m/z; 354 [M − H] 154LC/MS: condition 3, retention time = 1.64 min LC/MS (ESI⁺) m/z; 368 [M +H]⁺ 155 LC/MS: condition 3, retention time = 2.07 min LC/MS (ESI⁺) m/z;506 [M + H]⁺ LC/MS (ESI⁻) m/z; 504 [M − H]⁻

Pharmacological Assay

Now, a pharmacological assay of the tricyclic pyridine compounds of thepresent invention will be described.

Assay Example^(b) 1 Enzyme Assay

JAK1, JAK2, JAK3 and Tyk2 were purchased from Carna Biosciences, Inc. Asthe substrate, LANCE Ultra ULight-JAK1 Peptide (manufactured byPerkinElmer Co., Ltd. (PE)) was used. Dilute solutions of compounds andenzymes in assay buffer (50 mM HEPES pH7.5, 1 mM EGTA, 1 mM MgCl₂, 2 mMDTT, 0.01% Tween20) were dispensed into wells of a 384-well black plate.After 5 minutes of preincubation, dilute solutions of the substrate andATP (adenosine triphosphate) were added at a final concentration of 100μM, and the plate was incubated at room temperature for 2 hours. Afteraddition of a termination reagent containing EDTA (ehylenediaminetetraacetic acid) at a final concentration of 10 mM, LANCE Eu-W1024Anti-phosphotyrosine (PT66) (manufactured by PE) was added, and after 1hour of incubation, the fluorescences were measured with ARVO-HTS. Fromthe plot of logarithm of a compound concentration and inhibitoryactivity, the IC₅₀ was calculated. The results of JAK3, JAK1, JAK2 andTyk2 enzyme assays of the compounds of Synthetic Examples^(b) are shownin Tables^(b) 78 to 81. “*” in the Tables indicates IC₅₀>1 μM.

TABLE^(b) 78 Ex^(b). IC₅₀ (μM) IC₅₀ (μM) No. JAK3 JAK1  1 2.0 0.38  21.2 0.33  3 0.22 0.017  4 0.065 0.030  6a 0.031 0.027  6b 0.25 0.19  70.0032 0.0017  8 0.041 0.026  9 0.010 0.0040 10 0.034 0.0081 11 0.0340.012 12 1.3 0.13 13 1.3 0.042 16 0.11 0.038 17 0.69 0.027 18 1.2 0.04519 2.2 0.29 20 0.51 0.28

TABLE^(b) 79 Ex^(b). IC₅₀ (μM) IC₅₀ (μM) No. JAK2 TYK2  1 2.2 4.1  2 1.93.1  3 0.15 0.13  4 0.10 *  6a 0.046 0.63  6b 0.38 3.9  7 0.0040 0.060 8 0.075 1.5  9 0.0094 0.15 10 0.039 1.6 11 0.033 0.44 12 0.46 * 130.56 * 16 0.088 0.57 17 0.020 0.093 18 0.12 0.25 19 1.3 1.5 20 1.6 0.76

TABLE^(b) 80 IC₅₀ IC₅₀ IC₅₀ IC₅₀ Ex^(b). (μM) (μM) (μM) (μM) No. JAK1JAK2 JAK3 TYK2 21 0.56 1.3 0.82 * 22 0.33 0.28 0.37 * 23 0.035 0.220.10 * 24 0.025 0.74 0.56 * 25 0.055 0.23 0.070 0.70 26 0.0066 0.0480.10 0.41 27 0.018 0.040 0.042 0.43 28 0.31 2.0 2.3 7.9 29 0.015 0.190.20 0.41 30 0.18 * * * 31 0.24 * * * 32 0.081 0.77 0.55 * 33 0.00980.12 0.096 0.40 34 0.16 0.86 * * 35 0.018 0.089 0.11 0.99 36 0.000580.0032 0.0038 0.051 37 0.0015 0.0061 0.0028 0.062 38 0.0046 0.028 0.0310.27 39 0.048 0.15 0.18 * 40 0.088 0.50 0.26 * 41 0.20 0.29 0.32 * 420.016 0.15 0.093 * 43 0.030 0.16 0.15 0.51 44 0.014 0.15 0.057 0.84 450.012 0.038 0.040 0.44 46 0.033 0.21 0.046 * 47 0.11 0.23 0.11 * 48a0.14 1.0 * * 48b 0.094 0.46 0.36 * 49 0.0079 0.10 * * 50 0.0087 * * * 510.0050 0.36 * * 52 0.021 * * * 53 0.0074 0.048 0.047 0.040 54 0.00300.032 0.47 0.32 55 0.0012 0.020 0.21 0.22 56 0.019 0.24 * * 57 0.0130.25 * 0.86 58 0.037 0.57 * * 59 0.042 0.16 2.1 4.3 60 0.35 0.48 * * 610.077 0.22 5.4 3.6 62 0.054 0.36 * * 63 0.12 * * * 64 0.012 0.020 0.220.17 65 0.19 0.11 9.5 2.9 66 0.080 0.14 * 0.99 68 0.50 2.4 9.1 * 690.036 0.46 * 0.30 70 0.16 * * * 71 0.0019 0.036 0.46 0.38 72 0.00980.33 * 0.88 73 0.053 * * * 74 0.0050 0.069 0.86 0.84 75 0.0089 0.062 * *76 0.028 0.45 * * 77 0.0079 0.077 1.0 * 78 0.0039 0.066 * * 79 0.000400.0063 0.094 0.12 80 0.0016 0.020 0.34 0.24 81 0.000084 0.0016 0.0310.034 82 0.0021 0.021 0.32 0.32 83 0.0052 0.043 0.62 0.81 84 0.000750.017 0.13 0.33 85 0.075 0.68 * * 86 0.043 * * * 87 0.025 0.38 * *

TABLE^(b) 81 Ex^(b). IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) No. JAK1JAK2 JAK3 TYK2 88 0.082 * * * 89 0.011 * * * 90 0.22 * * * 910.083 * * * 92 0.097 * * * 93 0.37 * * * 94 0.034 * * 0.93 95 0.0170.34 * * 96 0.019 * * * 97 0.23 * * * 98 0.021 0.67 * * 99 0.069 * * *100 0.0066 0.046 * 0.45 101 0.015 0.40 * 0.46 102 0.0028 0.080 0.320.091 103 0.0043 0.083 * 0.12 104 0.034 0.046 0.38 0.38 105 3.2 * * *106 0.047 0.25 0.61 0.38 107 0.31 0.60 0.41 * 108 0.37 * * * 1090.92 * * * 110 0.42 * * * 111 0.44 * * * 112 0.0026 0.25 * 0.032 1130.0033 0.22 * 0.19 114 0.010 0.23 0.52 0.25 115 0.030 * * * 116 0.00120.012 0.036 0.039 117 0.030 0.85 * 0.80 118 0.027 0.34 * * 1190.039 * * * 120 0.029 0.73 * * 121 0.0074 0.21 * * 122 0.0032 0.49 * *123 0.15 * * * 124 0.025 0.61 * * 125 0.020 0.43 * * 126 0.028 0.36 * *127 0.0055 0.19 * 0.12 128 0.067 * * * 129 0.0079 0.18 0.81 0.36 1300.048 * * * 131 0.036 * * 0.78 132 0.0092 0.32 * * 133 0.012 0.27 * 0.41134 0.0020 0.025 0.81 0.032 135 0.0049 0.060 0.50 0.33 136 0.0032 0.0510.75 0.32 137 0.057 * 0.91 * 138 0.040 0.42 0.51 * 139 0.10 0.77 * * 1400.018 0.25 0.78 0.36 141 0.046 0.23 0.80 0.60 142 0.34 * * * 143 0.0730.85 * * 144 0.053 0.70 * * 145 0.047 0.69 * * 146 0.21 * * * 147 0.0980.82 * * 148 0.44 * * * 149 0.27 * * * 150 0.092 0.23 0.64 * 1510.21 * * * 152 0.067 0.21 0.48 * 153 0.33 * * * 154 0.29 * * * 1550.0021 0.055 0.20 0.14

The tricyclic pyridine compounds of the present invention have favorableinhibitory activity against JAKs as shown above.

Assay Example^(b) 2 Signal Assay in Human Whole Blood

To be a effective pharmaceutical compound for the target diseases of thepresent invention, especially for rheumatoid arthritis, it is morefavorable that the compounds indicate excellent inhibitory activityagainst JAKs in human whole blood. Inhibitory activity against JAKs inhuman whole blood can be assessed by, for example, STAT phosphorylationassay in human whole blood as described below.

Compounds are added at the various concentrations to human whole bloodwhich is collected from healthy volunteers and preincubated for 30minutes. Next, cytokine such as IL-2 or IL-6 is added to the mixture andincubated for 15 minutes. Cytokines can be purchased, for example, fromPeproTech Inc. Cytokines are added to mixture at 100 ng/mL as finalconcentration. The mixture including the blood cells are hemolyzed,fixed, permeabilized, washed, and resuspended in stain buffer. BDCytofix/Cytoperm® solution (manufactured by Becton, Dickinson andCompany (BD)), for example, can be used to hemolyze, fix, andpermeabilize. Staining buffer (manufactured by BD), for example, can beused as stain buffer according to each protocol issued by BD.Fluorescence-labeled anti-phosphorylated STAT antibody andfluorescence-labeled anti-CD3 antibody are added to the cell suspensionand incubated for 30 minutes. Then, cells are washed and resuspended instain buffer. Fluorescence-labeled anti-phosphorylated STAT antibody andfluorescence-labeled anti-CD3 antibody can be purchased, for examplefrom BD, and final concentration of antibodies can be determinedaccording to each protocols issued by BD. Fluorescence intensity offluorescence-labeled cells in cell suspension is detected byflow-cytometory. Because the detected fluorescence intensity isproportional to the concentration of the phosphorylated STAT protein inCD3 positive cells, inhibitory activity against STAT phosphorylation bythe compounds can be calculated from the ratio between the abovementioned fluorescence intensity and the blank fluorescence intensitywhich is measured simultaneously without the compounds. From the plot oflogarithm of the compound concentrations and the inhibitory activities,the IC₅₀ value can be calculated.

Assay Example^(b) 3 Inhibition of Proliferation of Erythro-Leukemic CellLine

The inhibitory activity of the tricyclic pyridine compounds of thepresent invention on cell proliferation mediated by JAK signal can beassayed using a human erythro-leukemic cell line, TF-1.

TF-1 cells can be purchased from ATCC (American Type CultureCollection). TF-1 cells can be expanded in RPMI1640 media containing 5%FBS and 1 ng/mL GM-CSF (Granulocyte Macrophage Colony-StimulatingFactor) using a CO₂ incubator (5% CO₂, 37° C.). At the assay, TF-1 cellswashed by PBS (Phosphate Buffered Saline) are resuspended in RPMI1640media containing 5% FBS, and dispensed in 96-well culture plate at 1×10⁴cells/well. Compounds at various concentrations are added to the cellsand preincubated for 30 minutes, and then cytokine such as IL-4 or IL-6is added to the cells. Culture plates are incubated using a CO₂incubator (5% CO₂, 37° C.) for 3 days. Cell proliferation can be assayedusing WST-8 reagent (Kishida Chemical Co., Ltd.) according toinstructions by the manufacturer. The formazan pigment is generated bythe addition of WST-8 reagent solution to each well of the cultureplates and the subsequent incubation in a CO₂ incubator (5% CO₂, 37° C.)for 4 hours, and then detected by measuring the absorbance at 450 nmwith a microplate reader. From the plot of logarithm of the compoundconcentrations and the inhibitory activities, the IC₅₀ value can becalculated.

Now, examples of formulations of tricyclic pyrimidine compoundsrepresented by the formula (I^(a)) and tricyclic pyridine compoundsrepresented by the formula (I^(b)) of the present invention (hereinafterreferred to collectively as compounds represented by the formula (I))will be shown.

Formulation Example 1

A granule preparation containing the following ingredients is prepared.

Ingredients Compound represented by the formula (I)  10 mg Lactose 700mg Corn Starch 274 mg HPC-L  16 mg Total 1000 mg 

A compound represented by the formula (I) and lactose are sifted througha 60-mesh sieve. Corn starch is sifted though a 120-mesh sieve. They aremixed in a V-type blender. The powder mixture is kneaded with alow-viscosity hydroxypropylcellulose (HPC-L) aqueous solution,granulated (extrusion granulation, die size 0.5-1 mm) and dried. Theresulting dry granules are sifted through a shaking sieve (12/60 mesh)to obtain a granule preparation.

Formulation Example 2

A powder preparation for capsulation containing the followingingredients is prepared.

Ingredients Compound represented by the formula (I) 10 mg Lactose 79 mgCorn Starch 10 mg Magnesium Stearate  1 mg Total 100 mg 

A compound represented by the formula (I) and lactose are sifted througha 60-mesh sieve. Corn starch is sifted though a 120-mesh sieve. They aremixed with magnesium stearate in a V-type blender. The 10% powder is putin hard gelatin capsules No. 5, 100 mg each.

Formulation Example 3

A granule preparation for capsulation containing the followingingredients is prepared.

Ingredients Compound represented by the formula (1) 15 mg Lactose 90 mgCorn Starch 42 mg HPC-L  3 mg Total 150 mg 

A compound represented by the formula (I) and lactose are sifted througha 60-mesh sieve. Corn starch is sifted though a 120-mesh sieve. They aremixed in a V-type blender. The powder mixture is kneaded with alow-viscosity hydroxypropylcellulose (HPC-L) aqueous solution,granulated and dried. The resulting dry granules are sifted through ashaking sieve (12/60 mesh). The granules are put in hard gelatincapsules No. 4, 150 mg each.

Formulation Example 4

A tablet preparation containing the following ingredients is prepared.

Ingredients Compound represented by the formula (I) 10 mg Lactose 90 mgMicrocrystalline cellulose 30 mg Magnesium Stearate  5 mg CMC-Na 15 mgTotal 150 mg 

A compound represented by the formula (I), lactose, microcrystallinecellulose and CMC-Na (carboxymethylcellulose sodium salt) are siftedthrough a 60-mesh sieve and mixed. The powder mixture is mixed withmagnesium stearate to give a bulk powder mixture. The powder mixture iscompressed directly into 150 mg tablets.

Formulation Example 5

An intravenous preparation is prepared as follows.

Compound represented by the formula (I)  100 mg Saturated Fatty AcidGlyceride 1000 ml

Solutions having the above-mentioned composition are usuallyadministered to a patient intravenously at a rate of 1 ml per 1 minute.

INDUSTRIAL APPLICABILITY

The compounds of the present invention have excellent JAK inhibitoryactivities and are useful for prevention or treatment of autoimmunediseases, especially rheumatoid arthritis, inflammatory diseases andallergic diseases.

1. A compound represented by the formula (I^(b)):

[wherein the ring A^(b) is represented by the formula (II^(b)):

(wherein T^(1b) is CR^(4b)R^(5b), C(═O), C(═S), C(═NR^(17b)), a sulfur atom, S(═O) or S(═O)₂, U^(1b) is a nitrogen atom or CR^(6b), and W^(1b) is a nitrogen atom or CR^(8b)), the formula (III^(b)):

(wherein T^(2b) is CR^(4b), U^(2b) is a nitrogen atom or CR^(6b), and W^(2b) is CR^(8b)R^(9b), C(═O), C(═S), C(═NR^(17b)), NR^(10b), an oxygen atom, a sulfur atom, S(═O) or S(═O)₂ (provided that when U^(2b) is CR^(6b), W^(2b) is not C(═O))) or the formula (IV^(b)):

(wherein T^(3b) is CR^(4b)R^(5b), C(═O), C(═S), C(═NR^(17b)), a sulfur atom, S(═O) or S(═O)₂, U^(3b) is CR^(6b)R^(7b), C(═O), C(═S), C(═NR^(17b)), NR^(10b), an oxygen atom, a sulfur atom, S(═O) or S(═O)₂, and W^(3b) is CR^(8b)R^(9b), C(═O), C(═S), C(═NR^(17b)), NR^(11b), an oxygen atom, a sulfur atom, S(═O) or S(═O)₂ (provided that when T^(3b) is CR^(4b)R^(5b) and U^(3b) is CR^(6b)R^(7b), W^(3b) is not CR^(8b)R^(9b))), X^(b) is a nitrogen atom or CR^(15b), Y^(b) is CR^(16b), R^(1b) is a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group or a C₁₋₆ haloalkyl group, the ring B^(b) is a C₃₋₁₁ cycloalkane, a C₃₋₁₁ cycloalkene, a 3 to 11-membered non-aromatic heterocycle, a C₆₋₁₄ aromatic carbocycle or a 5 to 10-membered aromatic heterocycle, L^(1b) is a single bond, a C₁₋₆ alkylene group, a C₂₋₆ alkenylene group or a C₂₋₆ alkynylene group (the C₁₋₆ alkylene group, the C₂₋₆ alkenylene group and the C₂₋₆ alkynylene group are unsubstituted or substituted with one or more identical or different substituents independently selected from the group consisting of halogen atoms, hydroxy groups, amino groups, cyano groups and nitro groups), L^(2b) is a single bond, a C₁₋₆ alkylene group, a C₂₋₆ alkenylene group or a C₂₋₆ alkynylene group (the C₁₋₆ alkylene group, the C₂₋₆ alkenylene group and the C₂₋₆ alkynylene group are unsubstituted or substituted with one or more identical or different substituents independently selected from the group consisting of halogen atoms, hydroxy groups, amino groups, cyano groups and nitro groups), L^(3b) is a single bond or represented by any of the following formulae (V^(b)-1) to (V^(b)-20):

(wherein E^(1b) is an oxygen atom, a sulfur atom or NR^(18b)), when L^(3b) is a single bond, R^(2b) is a hydrogen atom, a halogen atom, a C₃₋₁₁ cycloalkyl group, a 3 to 14-membered non-aromatic heterocyclyl group, a C₆₋₁₄ aryl group, a 5 to 10-membered aromatic heterocyclyl group, a 8 to 14-membered partially saturated aromatic cyclic group or a 8 to 14-membered aromatic ring-condensed alicyclic hydrocarbon group (the C₃₋₁₁ cycloalkyl group, the 3 to 14-membered non-aromatic heterocyclyl group, the C₆₋₁₄ aryl group, the 5 to 10-membered aromatic heterocyclyl group, the 8 to 14-membered partially saturated aromatic cyclic group and the 8 to 14-membered aromatic ring-condensed alicyclic hydrocarbon group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(4b) and the substituent set V^(9b)), when L^(3b) is not a single bond, R^(2b) is a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group (the C₁₋₆ alkyl group and the C₂₋₆ alkenyl group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(6b) and the substituent set V^(9b)), a C₃₋₁₁ cycloalkyl group, a 3 to 14-membered non-aromatic heterocyclyl group, a C₆₋₁₄ aryl group, a 5 to 10-membered aromatic heterocyclyl group, a 8 to 14-membered partially saturated aromatic cyclic group or a 8 to 14-membered aromatic ring-condensed alicyclic hydrocarbon group (the C₃₋₁₁ cycloalkyl group, the 3 to 14-membered non-aromatic heterocyclyl group, the C₆₋₁₄ aryl group, the 5 to 10-membered aromatic heterocyclyl group, the 8 to 14-membered partially saturated aromatic cyclic group and the 8 to 14-membered aromatic ring-condensed alicyclic hydrocarbon group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(4b) and substituent set V^(9b)), n^(b) is 0, 1 or 2, R^(3b) is a hydroxy group, an amino group, a carboxy group, a carbamoyl group, a sulfamoyl group, a phosphono group, a phosphonooxy group, a sulfo group, a sulfoxy group, a tetrazolyl group, a halogen atom, a cyano group, a nitro group, a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group, a C₃₋₁₁ cycloalkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ haloalkenyl group, a C₁₋₆ alkoxy group, a C₁₋₆ haloalkoxy group, a C₁₋₆ alkylthio group, a C₁₋₆ haloalkylthio group, a C₁₋₆ alkylcarbonyl group, a C₁₋₆ haloalkylcarbonyl group, a C₁₋₆ alkylsulfonyl group, a C₁₋₆ haloalkylsulfonyl group, a C₁₋₆ alkoxycarbonyl group, a mono-C₁₋₆ alkylamino group, a di-C₁₋₆ alkylamino group, a mono-C₁₋₆ alkylaminocarbonyl group, a di-C₁₋₆ alkylaminocarbonyl group or a C₁₋₆ alkylcarbonylamino group (when n^(b) is 2, R^(3b)'s may be identical or different), each of R^(4b), R^(5b), R^(6b), R^(7b), R^(8b) and R^(9b) is independently a hydrogen atom, a hydroxy group, an amino group, a carboxy group, a carbamoyl group, a tetrazolyl group, a halogen atom, a cyano group, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthio group, a C₁₋₆ alkylcarbonyl group, a C₁₋₆ alkylsulfonyl group, a mono-C₁₋₆ alkylamino group, a di-C₁₋₆ alkylamino group (the C₁₋₆ alkyl group, the C₂₋₆ alkenyl group, the C₁₋₆ alkoxy group, the C₁₋₆ alkylthio group, the C₁₋₆ alkylcarbonyl group, the C₁₋₆ alkylsulfonyl group, the mono-C₁₋₆ alkylamino group and the di-C₁₋₆ alkylamino group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(3b)), a C₁₋₆ alkoxycarbonyl group, a C₃₋₁₁ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclyl group, a C₆₋₁₄ aryl group or a 5 to 10-membered aromatic heterocyclyl group (the C₃₋₁₁ cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclyl group, the C₆₋₁₄ aryl group and the 5 to 10-membered aromatic heterocyclyl group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(1b)), each of R^(10b) and R^(11b) is independently a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkylcarbonyl group, a C₁₋₆ alkylsulfonyl group, a C₁₋₆ alkoxycarbonyl group, a mono-C₁₋₆ alkylaminocarbonyl group, a di-C₁₋₆ alkylaminocarbonyl group (the C₁₋₆ alkyl group, the C₂₋₆ alkenyl group, the C₁₋₆ alkylcarbonyl group, the C₁₋₆ alkylsulfonyl group, the C₁₋₆ alkoxycarbonyl group, the mono-C₁₋₆ alkylaminocarbonyl group and the di-C₁₋₆ alkylaminocarbonyl group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(3b)), a C₃₋₁₁ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclyl group, a C₆₋₁₄ aryl group or a 5 to 10-membered aromatic heterocyclyl group (the C₃₋₁₁ cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclyl group, the C₆₋₁₄ aryl group and the 5 to 10-membered aromatic heterocyclyl group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(1b)), each of R^(12b), R^(13b) and R^(14b) is independently a hydrogen atom, a C₁₋₆ alkyl group or a C₁₋₆ haloalkyl group (the C₁₋₆ alkyl group and the C₁₋₆ haloalkyl group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(3b), the substituent set V^(8b) and the substituent set V^(9b)), each of R^(15b) and R^(16b) is independently a hydrogen atom, a halogen atom, a cyano group, a carbamoyl group, a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group, a C₃₋₁₁ cycloalkyl group, a C₁₋₆ alkoxy group, a C₁₋₆ haloalkoxy group, a C₁₋₆ alkylthio group, a C₁₋₆ alkylcarbonyl group, a C₁₋₆ alkylsulfonyl group, a 3 to 11-membered non-aromatic heterocyclyl group, a C₆₋₁₄ aryl group or a 5 to 10-membered aromatic heterocyclyl group, each of R^(17b) and R^(18b) is independently a hydrogen atom, a hydroxy group, a cyano group, a nitro group, a C₁₋₆ alkyl group or a C₁₋₆ alkoxy group, the substituent set V^(1b) consists of hydroxy groups, amino groups, carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups, phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups, halogen atoms, cyano groups, nitro groups, C₁₋₆ alkyl groups, C₁₋₆ haloalkyl groups, C₃₋₁₁ cycloalkyl groups, C₂₋₆ alkenyl groups, C₂₋₆ haloalkenyl groups, C₁₋₆ alkoxy groups, C₁₋₆ haloalkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆ haloalkylthio groups, C₁₋₆ alkylcarbonyl groups, C₁₋₆ haloalkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆ haloalkylsulfonyl groups, C₁₋₆ alkoxycarbonyl groups, 3 to 11-membered non-aromatic heterocyclyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups and C₁₋₆ alkylcarbonylamino groups, the substituent set V^(2b) consists of the groups in the substituent set V^(1b), and C₆₋₁₄ aryl groups and 5 to 10-membered aromatic heterocyclyl groups (the C₆₋₁₄ aryl groups and the 5 to 10-membered aromatic heterocyclyl groups are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(1b)), the substituent set V^(3b) consists of hydroxy groups, amino groups, carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups, phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups, halogen atoms, cyano groups, nitro groups, C₁₋₆ alkoxy groups, C₁₋₆ haloalkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆ haloalkylthio groups, C₁₋₆ alkylcarbonyl groups, C₁₋₆ haloalkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆ haloalkylsulfonyl groups, C₁₋₆ alkoxycarbonyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups, C₁₋₆ alkylcarbonylamino groups, C₃₋₁₁ cycloalkyl groups, 3 to 11-membered non-aromatic heterocyclyl groups, C₆₋₁₄ aryl group and 5 to 10-membered aromatic heterocyclyl groups (the C₃₋₁₁ cycloalkyl groups, the 3 to 11-membered non-aromatic heterocyclyl groups, the C₆₋₁₄ aryl groups and the 5 to 10-membered aromatic heterocyclyl groups are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(1b)), the substituent set V^(4b) consists of hydroxy groups, amino groups, carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups, phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups, halogen atoms, cyano groups, nitro groups, C₁₋₆ alkyl groups, C₂₋₆ alkenyl groups, C₁₋₆ alkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆ alkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆ alkoxycarbonyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups, C₁₋₆ alkylcarbonylamino groups (the C₁₋₆ alkyl groups, the C₂₋₆ alkenyl groups, the C₁₋₆ alkoxy groups, the C₁₋₆ alkylthio groups, the C₁₋₆ alkylcarbonyl groups, the C₁₋₆ alkylsulfonyl groups, the C₁₋₆ alkoxycarbonyl groups, the mono-C₁₋₆ alkylamino groups, the di-C₁₋₆ alkylamino groups, the mono-C₁₋₆ alkylaminocarbonyl groups, the di-C₁₋₆ alkylaminocarbonyl groups and the C₁₋₆ alkylcarbonylamino groups are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(3b)), C₃₋₁₁ cycloalkyl groups, 3 to 11-membered non-aromatic heterocyclyl groups, C₆₋₁₄ aryl groups and 5 to 10-membered aromatic heterocyclyl groups (the C₃₋₁₁ cycloalkyl groups, the 3 to 11-membered non-aromatic heterocyclyl groups, the C₆₋₁₄ aryl groups and the 5 to 10-membered aromatic heterocyclyl groups are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(1b)), the substituent set V^(5b) consists of hydroxy groups, amino groups, carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups, phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups, halogen atoms, cyano groups, nitro groups, C₁₋₆ alkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆ alkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆ alkoxycarbonyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups, C₁₋₆ alkylcarbonylamino groups, C₃₋₁₁ cycloalkyl groups, 3 to 11-membered non-aromatic heterocyclyl groups, C₆₋₁₄ aryl groups and 5 to 10-membered aromatic heterocyclyl groups (the C₁₋₆ alkoxy groups, the C₁₋₆ alkylthio groups, the C₁₋₆ alkylcarbonyl groups, the C₁₋₆ alkylsulfonyl groups, the C₁₋₆ alkoxycarbonyl groups, the mono-C₁₋₆ alkylamino groups, the di-C₁₋₆ alkylamino groups, the mono-C₁₋₆ alkylaminocarbonyl groups, the di-C₁₋₆ alkylaminocarbonyl groups, the C₁₋₆ alkylcarbonylamino groups, the C₃₋₁₁ cycloalkyl groups, the 3 to 11-membered non-aromatic heterocyclyl groups, the C₆₋₁₄ aryl groups and the 5 to 10-membered aromatic heterocyclyl groups are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(3b)), the substituent set V^(6b) consists of hydroxy groups, amino groups, carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups, phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups, halogen atoms, cyano groups, nitro groups, C₁₋₆ alkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆ alkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆ alkoxycarbonyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups, C₁₋₆ alkylcarbonylamino groups (the C₁₋₆ alkoxy groups, the C₁₋₆ alkylthio groups, the C₁₋₆ alkylcarbonyl groups, the C₁₋₆ alkylsulfonyl groups, the C₁₋₆ alkoxycarbonyl groups, the mono-C₁₋₆ alkylamino groups, the di-C₁₋₆ alkylamino groups, the mono-C₁₋₆ alkylaminocarbonyl groups, the di-C₁₋₆ alkylaminocarbonyl groups and the C₁₋₆ alkylcarbonylamino groups are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(3b)), C₃₋₁₁ cycloalkyl groups, 3 to 11-membered non-aromatic heterocyclyl groups, C₆₋₁₄ aryl groups, 5 to 10-membered aromatic heterocyclyl groups, 8 to 14-membered partially saturated aromatic cyclic groups and 8 to 14-membered aromatic ring-condensed alicyclic hydrocarbon groups (the C₃₋₁₁ cycloalkyl groups, the 3 to 11-membered non-aromatic heterocyclyl groups, the C₆₋₁₄ aryl groups, the 5 to 10-membered aromatic heterocyclyl groups, the 8 to 14-membered partially saturated aromatic cyclic groups and the 8 to 14-membered aromatic ring-condensed alicyclic hydrocarbon groups are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(4b) and the substituent set V^(9b)), and the substituent set V^(8b) consists of 8 to 14-membered partially saturated aromatic cyclic groups and 8 to 14-membered aromatic ring-condensed alicyclic hydrocarbon groups (the 8 to 14-membered partially saturated aromatic cyclic groups and the 8 to 14-membered aromatic ring-condensed alicyclic hydrocarbon groups are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(2b)), the substituent set V^(9b) consists of, mono-C₁₋₆ alkylaminosulfonyl groups, di-C₁₋₆ alkylaminosulfonyl groups, C₁₋₆ alkylsulfonylamino groups (the mono-C₁₋₆ alkylaminosulfonyl groups, di-C₁₋₆ alkylaminosulfonyl groups and C₁₋₆ alkylsulfonylamino groups are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(3b)), C₃₋₆ cycloalkoxy groups, C₃₋₆ cycloalkylamino groups, C₃₋₆ cycloalkylthio groups, C₃₋₆ cycloalkylcarbonyl groups and C₃₋₆ cycloalkylsulfonyl groups (the C₃₋₆ cycloalkoxy groups, the C₃₋₆ cycloalkylamino groups, the C₃₋₆ cycloalkylthio groups, the C₃₋₆ cycloalkylcarbonyl groups and the C₃₋₆ cycloalkylsulfonyl groups unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(2b))], a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 2. The compound according to claim 1, which is represented by the formula (I^(b)):

[wherein the ring A^(b) is represented by the formula (II^(b)):

(wherein T^(1b) is CR^(4b)R^(5b), C(═O), C(═S), C(═NR^(17b)), a sulfur atom, S(═O) or S(═O)₂, U^(1b) is a nitrogen atom or CR^(6b), and W^(1b) is a nitrogen atom or CR^(8b)), the formula (III^(b)):

(wherein T^(2b) is CR^(4b), U^(2b) is a nitrogen atom or CR^(6b), and W^(2b) is CR^(8b)R^(9b), C(═O), C(═S), C(═NR^(17b)), NR^(10b), an oxygen atom, a sulfur atom, S(═O) or S(═O)₂ (provided that when U^(2b) is CR^(6b), W^(2b) is not C(═O))), or the formula (IV^(b)):

(wherein T^(3b) is CR^(4b)R^(5b), C(═O), C(═S), C(═NR^(17b)), a sulfur atom, S(═O) or S(═O)₂, U^(3b) is CR^(6b)R^(7b), C(═O), C(═S), C(═NR^(17b)), NR^(10b), an oxygen atom, a sulfur atom, S(═O) or S(═O)₂, and W^(3b) is CR^(8b)R^(9b), C(═O), C(═S), C(═NR^(17b)), NR^(11b), an oxygen atom, a sulfur atom, S(═O) or S(═O)₂ (provided that when T^(3b) is CR^(4b)R^(5b) and U^(3b) is CR^(6b)R^(7b), W^(3b) is not CR^(8b)R^(9b))), X^(b) is a nitrogen atom or CR^(15b), Y^(b) is CR^(16b), R^(1b) is a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group or a C₁₋₆ haloalkyl group, the ring B^(b) is a C₃₋₁₁ cycloalkane, a C₃₋₁₁ cycloalkene, a 3 to 11-membered non-aromatic heterocycle, a C₆₋₁₄ aromatic carbocycle or a 5 to 10-membered aromatic heterocycle, L^(1b) is a single bond, a C₁₋₆ alkylene group, a C₂₋₆ alkenylene group or a C₂₋₆ alkynylene group (the C₁₋₆ alkylene group, the C₂₋₆ alkenylene group and the C₂₋₆ alkynylene group are unsubstituted or substituted with one or more identical or different substituents independently selected from the group consisting of halogen atoms, hydroxy groups, amino groups, cyano groups and nitro groups), L^(2b) is a single bond, a C₁₋₆ alkylene group, a C₂₋₆ alkenylene group or a C₂₋₆ alkynylene group (the C₁₋₆ alkylene group, the C₂₋₆ alkenylene group and the C₂₋₆ alkynylene group are unsubstituted or substituted with one or more identical or different substituents independently selected from the group consisting of halogen atoms, hydroxy groups, amino groups, cyano groups and nitro groups), L^(3b) is a single bond or represented by any of the following formulae (V^(b)-1) to (V^(b)-20):

(wherein E^(1b) is an oxygen atom, a sulfur atom or NR^(18b)), when L^(3b) is a single bond, R^(2b) is a hydrogen atom, a halogen atom, a C₃₋₁₁ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclyl group, a C₆₋₁₄ aryl group or a 5 to 10-membered aromatic heterocyclyl group (the C₃₋₁₁ cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclyl group, the C₆₋₁₄ aryl group and the 5 to 10-membered aromatic heterocyclyl group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(4b)), when L^(3b) is not a single bond, R^(2b) is a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group (the C₁₋₆ alkyl group and the C₂₋₆ alkenyl group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(5b)), a C₃₋₁₁ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclyl group, a C₆₋₁₄ aryl group or a 5 to 10-membered aromatic heterocyclyl group (the C₃₋₁₁ cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclyl group, the C₆₋₁₄ aryl group and the 5 to 10-membered aromatic heterocyclyl group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(4b)), n^(b) is 0, 1 or 2, R^(3b) is a hydroxy group, an amino group, a carboxy group, a carbamoyl group, a sulfamoyl group, a phosphono group, a phosphonooxy group, a sulfo group, a sulfoxy group, a tetrazolyl group, a halogen atom, a cyano group, a nitro group, a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group, a C₃₋₁₁ cycloalkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ haloalkenyl group, a C₁₋₆ alkoxy group, a C₁₋₆ haloalkoxy group, a C₁₋₆ alkylthio group, a C₁₋₆ haloalkylthio group, a C₁₋₆ alkylcarbonyl group, a C₁₋₆ haloalkylcarbonyl group, a C₁₋₆ alkylsulfonyl group, a C₁₋₆ haloalkylsulfonyl group, a C₁₋₆ alkoxycarbonyl group, a mono-C₁₋₆ alkylamino group, a di-C₁-6 alkylamino group, a mono-C₁₋₆ alkylaminocarbonyl group, a di-C₁₋₆ alkylaminocarbonyl group or a C₁₋₆ alkylcarbonylamino group (when n^(b) is 2, R^(3b)'s may be identical or different), each of R^(4b), R^(5b), R^(6b), R^(7b), R^(8b) and R^(9b) is independently a hydrogen atom, a hydroxy group, an amino group, a carboxy group, a carbamoyl group, a tetrazolyl group, a halogen atom, a cyano group, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthio group, a C₁₋₆ alkylcarbonyl group, a C₁₋₆ alkylsulfonyl group, a mono-C₁₋₆ alkylamino group, a di-C₁₋₆ alkylamino group (the C₁₋₆ alkyl group, the C₂₋₆ alkenyl group, the C₁₋₆ alkoxy group, the C₁₋₆ alkylthio group, the C₁₋₆ alkylcarbonyl group, the C₁₋₆ alkylsulfonyl group, the mono-C₁₋₆ alkylamino group and the di-C₁₋₆ alkylamino group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(3b)), a C₁₋₆ alkoxycarbonyl group, a C₃₋₁₁ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclyl group, a C₆₋₁₄ aryl group or a 5 to 10-membered aromatic heterocyclyl group (the C₃₋₁₁ cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclyl group, the C₆₋₁₄ aryl group and the 5 to 10-membered aromatic heterocyclyl group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(1b)), each of R^(10b) and R^(11b) is independently a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkylcarbonyl group, a C₁₋₆ alkylsulfonyl group, a C₁₋₆ alkoxycarbonyl group, a mono-C₁₋₆ alkylaminocarbonyl group, a di-C₁₋₆ alkylaminocarbonyl group (the C₁₋₆ alkyl group, the C₂₋₆ alkenyl group, the C₁₋₆ alkylcarbonyl group, the C₁₋₆ alkylsulfonyl group, the C₁₋₆ alkoxycarbonyl group, the mono-C₁₋₆ alkylaminocarbonyl group and the di-C₁₋₆ alkylaminocarbonyl group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(3b)), a C₃₋₁₁ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclyl group, a C₆₋₁₄ aryl group or a 5 to 10-membered aromatic heterocyclyl group (the C₃₋₁₁ cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclyl group, the C₆₋₁₄ aryl group and the 5 to 10-membered aromatic heterocyclyl group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(1b)), each of R^(12b), R^(13b) and R^(14b) is independently a hydrogen atom, a C₁₋₆ alkyl group or a C₁₋₆ haloalkyl group (the C₁₋₆ alkyl group and the C₁₋₆ haloalkyl group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(3b)), each of R^(15b) and R^(16b) is independently a hydrogen atom, a halogen atom, a cyano group, a carbamoyl group, a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group, a C₃₋₁₁ cycloalkyl group, a C₁₋₆ alkoxy group, a C₁₋₆ haloalkoxy group, a C₁₋₆ alkylthio group, a C₁₋₆ alkylcarbonyl group, a C₁₋₆ alkylsulfonyl group, a 3 to 11-membered non-aromatic heterocyclyl group, a C₆₋₁₄ aryl group or a 5 to 10-membered aromatic heterocyclyl group, each of R^(17b) and R^(18b) is independently a hydrogen atom, a hydroxy group, a cyano group, a nitro group, a C₁₋₆ alkyl group or a C₁₋₆ alkoxy group, the substituent set V^(1b) consists of hydroxy groups, amino groups, carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups, phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups, halogen atoms, cyano groups, nitro groups, C₁₋₆ alkyl groups, C₁₋₆ haloalkyl groups, C₃₋₁₁ cycloalkyl groups, C₂₋₆ alkenyl groups, C₂₋₆ haloalkenyl groups, C₁₋₆ alkoxy groups, C₁₋₆ haloalkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆ haloalkylthio groups, C₁₋₆ alkylcarbonyl groups, C₁₋₆ haloalkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆ haloalkylsulfonyl groups, C₁₋₆ alkoxycarbonyl groups, 3 to 11-membered non-aromatic heterocyclyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups and C₁₋₆ alkylcarbonylamino groups, the substituent set V^(2b) consists of the groups in the substituent set V^(1b) and C₆₋₁₄ aryl groups and 5 to 10-membered aromatic heterocyclyl groups (the C₆₋₁₄ aryl groups and 5 to 10-membered aromatic heterocyclyl groups are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(1b)), the substituent set V^(3b) consists of hydroxy groups, amino groups, carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups, phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups, halogen atoms, cyano groups, nitro groups, C₁₋₆ alkoxy groups, C₁₋₆ haloalkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆ haloalkylthio groups, C₁₋₆ alkylcarbonyl groups, C₁₋₆ haloalkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆ haloalkylsulfonyl groups, C₁₋₆ alkoxycarbonyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups, C₁₋₆ alkylcarbonylamino groups, C₃₋₁₁ cycloalkyl groups, 3 to 11-membered non-aromatic heterocyclyl groups, C₆₋₁₄ aryl groups and 5 to 10-membered aromatic heterocyclyl groups (the C₃₋₁₁ cycloalkyl groups, the 3 to 11-membered non-aromatic heterocyclyl groups, the C₆₋₁₄ aryl groups and the 5 to 10-membered aromatic heterocyclyl groups are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(1b)), the substituent set V^(4b) consists of hydroxy groups, amino groups, carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups, phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups, halogen atoms, cyano groups, nitro groups, C₁₋₆ alkyl groups, C₂₋₆ alkenyl groups, C₁₋₆ alkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆ alkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆ alkoxycarbonyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups, C₁₋₆ alkylcarbonylamino groups (the C₁₋₆ alkyl groups, the C₂₋₆ alkenyl groups, the C₁₋₆ alkoxy groups, the C₁₋₆ alkylthio groups, the C₁₋₆ alkylcarbonyl groups, the C₁₋₆ alkylsulfonyl groups, the C₁₋₆ alkoxycarbonyl groups, the mono-C₁₋₆ alkylamino groups, the di-C₁₋₆ alkylamino groups, the mono-C₁₋₆ alkylaminocarbonyl groups, the di-C₁₋₆ alkylaminocarbonyl groups and the C₁₋₆ alkylcarbonylamino groups are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(3b)), C₃₋₁₁ cycloalkyl groups, 3 to 11-membered non-aromatic heterocyclyl groups, C₆₋₁₄ aryl groups and 5 to 10-membered aromatic heterocyclyl groups (the C₃₋₁₁ cycloalkyl groups, the 3 to 11-membered non-aromatic heterocyclyl groups, the C₆₋₁₄ aryl groups and the 5 to 10-membered aromatic heterocyclyl groups are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(1b)), and the substituent set V^(5b) consists of hydroxy groups, amino groups, carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups, phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups, halogen atoms, cyano groups, nitro groups, C₁₋₆ alkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆ alkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆ alkoxycarbonyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups, C₁₋₆ alkylcarbonylamino groups, C₃₋₁₁ cycloalkyl groups, 3 to 11-membered non-aromatic heterocyclyl groups, C₆₋₁₄ aryl groups and 5 to 10-membered aromatic heterocyclyl groups (the C₁₋₆ alkoxy groups, the C₁₋₆ alkylthio groups, the C₁₋₆ alkylcarbonyl groups, the C₁₋₆ alkylsulfonyl groups, the C₁₋₆ alkoxycarbonyl groups, the mono-C₁₋₆ alkylamino groups, the di-C₁₋₆ alkylamino groups, the mono-C₁₋₆ alkylaminocarbonyl groups, the di-C₁₋₆ alkylaminocarbonyl groups, the C₁₋₆ alkylcarbonylamino groups, the C₃₋₁₁ cycloalkyl groups, the 3 to 11-membered non-aromatic heterocyclyl groups, the C₆₋₁₄ aryl groups and the 5 to 10-membered aromatic heterocyclyl groups are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(3b))], a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 3. The compound according to claim 2, wherein R^(1b) is a hydrogen atom, a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 4. The compound according to claim 2, wherein X^(b) is a nitrogen atom or CR^(15b) (wherein R^(15b) is a hydrogen atom, a halogen atom, a cyano group, a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group or a C₃₋₆ cycloalkyl group), and Y^(b) is CR^(16b) (wherein R^(16b) is a hydrogen atom), a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 5. The compound according to claim 4, wherein X^(b) is a nitrogen atom or CR^(15b) (wherein R^(15b) is a hydrogen atom or a halogen atom), a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 6. The compound according to claim 2, wherein the ring A^(b) is represented by the formula (II^(b)):

(wherein T^(1b) is CR^(4b)R^(5b), C(═O), C(═S) or S(═O)₂, U^(1b) is a nitrogen atom or CR^(6b), and W^(1b) is CR^(8b)), the formula (III^(b)):

(wherein T^(2b) is CR^(4b), U^(2b) is a nitrogen atom, and W^(2b) is C(═O) or C(═S)) or the formula (IV^(b)):

(wherein T^(3b) is C(═O), U^(3b) is NR^(10b) or an oxygen atom, and W is CR^(8b)R^(9b), C(═O) or C(═S)), a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 7. The compound according to claim 2, wherein the ring A^(b) is represented by any of the following formulae (XVIII^(b)-1) to (XVIII^(b)-8):

(wherein each of E^(2b) and E^(3b) is independently an oxygen atom or a sulfur atom, each of R^(4b), R^(5b), R^(6b), R^(8b) and R^(9b) is independently a hydrogen atom, a halogen atom or a C₁₋₃ alkyl group, and R^(10b) is a hydrogen atom or a C₁₋₃ alkyl group), a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 8. The compound according to claim 2, wherein L^(1b) is a single bond, L^(2b) is a single bond, a C₁₋₆ alkylene group or a C₂₋₆ alkenylene group (the C₁₋₆ alkylene group and the C₂₋₆ alkenylene group are unsubstituted or substituted with one or more identical or different substituents independently selected from the group consisting of a halogen atoms, hydroxy groups, amino groups, cyano groups and nitro groups), the ring B^(b) is a C₃₋₁₁ cycloalkane, a C₃₋₁₁ cycloalkene, a 3 to 11-membered non-aromatic heterocycle, a C₆₋₁₄ aromatic carbocycle or a 5 to 10-membered aromatic heterocycle, n^(b) is, 0 or 1, R^(3b) is a hydroxy group, an amino group, a halogen atom, a cyano group, a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group, a C₃₋₆ cycloalkyl group, a C₁₋₃ alkoxy group, a C₁₋₃ haloalkoxy group or a C₁₋₃ alkylsulfonyl group, L^(3b) is represented by any of the following formulae (V^(b)-1) to (V^(b)-20):

(wherein E^(1b) is an oxygen atom, a sulfur atom or NR^(18b)), R^(2b) is a hydrogen atom, a C₁₋₆ alkyl group or a C₂₋₆ alkenyl group (the C₁₋₆ alkyl group and the C₂₋₆ alkenyl group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(5b)), and the substituent set V^(5b) consists of hydroxy groups, amino groups, carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups, phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups, halogen atoms, cyano groups, nitro groups, C₁₋₆ alkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆ alkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆ alkoxycarbonyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups, C₁₋₆ alkylcarbonylamino groups, C₃₋₁₁ cycloalkyl groups, 3 to 11-membered non-aromatic heterocyclyl groups, C₆₋₁₄ aryl groups and 5 to 10-membered aromatic heterocyclyl groups (the C₁₋₆ alkoxy groups, the C₁₋₆ alkylthio groups, the C₁₋₆ alkylcarbonyl groups, the C₁₋₆ alkylsulfonyl groups, the C₁₋₆ alkoxycarbonyl groups, the mono-C₁₋₆ alkylamino groups, the di-C₁₋₆ alkylamino groups, the mono-C₁₋₆ alkylaminocarbonyl groups, the di-C₁₋₆ alkylaminocarbonyl groups, the C₁₋₆ alkylcarbonylamino groups, the C₃₋₁₁ cycloalkyl groups, the 3 to 11-membered non-aromatic heterocyclyl groups, the C₆₋₁₄ aryl groups and the 5 to 10-membered aromatic heterocyclyl groups are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(3b))], a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 9. The compound according to claim 2, wherein L^(1b) is a single bond or a C₁₋₃ alkylene group, L^(2b) is a single bond or a C₁₋₃ alkylene group (the C₁₋₃ alkylene group is unsubstituted or substituted with a cyano group or a C₁₋₃ haloalkyl group), the ring B^(b) is a C₃₋₁₁ cycloalkane, a C₃₋₁₁ cycloalkene, a 3 to 11-membered non-aromatic heterocycle, benzene or a 5 to 6-membered aromatic heterocycle, n^(b) is, 0 or 1, R^(3b) is a hydroxy group, an amino group, a carboxy group, a carbamoyl group, a tetrazolyl group, a halogen atom, a cyano group, a nitro group, a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group, a C₃₋₆ cycloalkyl group, a C₁₋₃ alkoxy group, a C₁₋₃ haloalkoxy group or a C₁₋₃ alkylsulfonyl group, L^(3b) is represented by any of the following formulae (V^(b)-1) to (V^(b)-6):

(wherein E^(1b) is an oxygen atom, a sulfur atom or NR^(18b)), R^(2b) is a hydrogen atom, a C₁₋₆ alkyl group, or a C₂₋₆ alkenyl group (the C₁₋₆ alkyl group and the C₂₋₆ alkenyl group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(5b)), and the substituent set V^(5b) consists of hydroxy groups, amino groups, carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups, phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups, halogen atoms, cyano groups, nitro groups, C₁₋₆ alkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆ alkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆ alkoxycarbonyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups, C₁₋₆ alkylcarbonylamino groups, C₃₋₁₁ cycloalkyl groups, 3 to 11-membered non-aromatic heterocyclyl groups, C₆₋₁₄ aryl groups and 5 to 10-membered aromatic heterocyclyl groups (the C₁₋₆ alkoxy groups, the C₁₋₆ alkylthio groups, the C₁₋₆ alkylcarbonyl groups, the C₁₋₆ alkylsulfonyl groups, the C₁₋₆ alkoxycarbonyl groups, the mono-C₁₋₆ alkylamino groups, the di-C₁₋₆ alkylamino groups, the mono-C₁₋₆ alkylaminocarbonyl groups, the di-C₁₋₆ alkylaminocarbonyl groups, the C₁₋₆ alkylcarbonylamino groups, the C₃₋₁₁ cycloalkyl groups, the 3 to 11-membered non-aromatic heterocyclyl groups, the C₆₋₁₄ aryl groups and the 5 to 10-membered aromatic heterocyclyl groups are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(3b))], a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 10. The compound according to claim 8, wherein the ring A^(b) is represented by the formula (IV^(b)), the ring B^(b) is a C₃₋₁₁ cycloalkane or a 4 to 7-membered non-aromatic heterocycle, n^(b) is 0 or 1, and L^(3b) is represented by any of the following formulae (V^(b)-1) to (V^(b)-6):

(wherein E^(1b) is an oxygen atom, a sulfur atom or NR^(18b)), a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 11. The compound according to claim 8, wherein the ring A^(b) is represented by the formula (IV^(b)), T^(3b) is C(═O), U^(3b) is NR^(10b), W^(3b) is C(═O), X^(b) is CR^(15b), the ring B^(b) is a C₃₋₁₁ cycloalkane, L^(1b) is a single bond, L^(2b) is a C₁₋₆ alkylene group, L^(3b) is represented by any of the following formulae (V^(b)-1) to (V^(b)-6):

(wherein E^(1b) is an oxygen atom, a sulfur atom or NR^(18b)), R^(2b) is a hydrogen atom, a C₁₋₆ alkyl group, or a C₂₋₆ alkenyl group (the C₁₋₆ alkyl group and the C₂₋₆ alkenyl group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(5b)), and the substituent set V^(5b) consists of hydroxy groups, amino groups, carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups, phosphonooxy groups, sulfo groups, sulfoxy groups, tetrazolyl groups, halogen atoms, cyano groups, nitro groups, C₁₋₆ alkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆ alkylcarbonyl groups, C₁₋₆ alkylsulfonyl groups, C₁₋₆ alkoxycarbonyl groups, mono-C₁₋₆ alkylamino groups, di-C₁₋₆ alkylamino groups, mono-C₁₋₆ alkylaminocarbonyl groups, di-C₁₋₆ alkylaminocarbonyl groups, C₁₋₆ alkylcarbonylamino groups, C₃₋₁₁ cycloalkyl groups, 3 to 11-membered non-aromatic heterocyclyl groups, C₆₋₁₄ aryl groups and 5 to 10-membered aromatic heterocyclyl groups (the C₁₋₆ alkoxy groups, the C₁₋₆ alkylthio groups, the C₁₋₆ alkylcarbonyl groups, the C₁₋₆ alkylsulfonyl groups, the C₁₋₆ alkoxycarbonyl groups, the mono-C₁₋₆ alkylamino groups, the di-C₁₋₆ alkylamino groups, the mono-C₁₋₆ alkylaminocarbonyl groups, the di-C₁₋₆ alkylaminocarbonyl groups, the C₁₋₆ alkylcarbonylamino groups, the C₃₋₁₁ cycloalkyl groups, the 3 to 11-membered non-aromatic heterocyclyl groups, the C₆₋₁₄ aryl groups and the 5 to 10-membered aromatic heterocyclyl groups are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(3b))], a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 12. The compound according to claim 8, wherein L^(2b) is a C₁₋₆ alkylene group, a C₂₋₃ alkenylene group (the C₁₋₆ alkylene group and the C₂₋₃ alkenylene group are unsubstituted or substituted with a cyano group) or C₁₋₆ haloalkylene group, and R^(2b) is a hydrogen atom, a C₁₋₆ alkyl group, or a C₂₋₆ alkenyl group (the C₁₋₆ alkyl group and the C₂₋₆ alkenyl group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(5b)), a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 13. The compound according to claim 2, wherein L^(1b) is a single bond, L^(2b) is a single bond, a C₁₋₆ alkylene group or a C₂₋₆ alkenylene group (the C₁₋₆ alkylene group and the C₂₋₆ alkenylene group are unsubstituted or substituted with one or more identical or different substituents independently selected from the group consisting of halogen atoms, hydroxy groups, amino groups, cyano groups and nitro groups), the ring B^(b) is a C₃₋₁₁ cycloalkane, a C₃₋₁₁ cycloalkene, a 3 to 11-membered non-aromatic heterocyclyl group, a C₆₋₁₄ aryl group or a 5 to 10-membered aromatic heterocycle, n^(b) is 0 or 1, R^(3b) is a hydroxy group, an amino group, a halogen atom, a cyano group, a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group, a C₃₋₆ cycloalkyl group, a C₁₋₃ alkoxy group or a C₁₋₃ haloalkoxy group, L^(3b) is represented by any of the following formulae (VI^(b)-1) to (VI^(b)-11):

(wherein E^(1b) is an oxygen atom or a sulfur atom, each of R^(12b) and R^(13b) is independently a hydrogen atom, a C₁₋₆ alkyl group or a C₁₋₆ haloalkyl group (the C₁₋₆ alkyl group and the C₁₋₆ haloalkyl group are unsubstituted or substituted with one or more identical or different substituents independently selected from the group consisting of halogen atoms, cyano groups, hydroxy group, C₁₋₆ alkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆ alkylsulfonyl groups, C₃₋₆ cycloalkyl groups, 4 to 7-membered non-aromatic heterocyclyl groups, phenyl groups and 5 to 6-membered aromatic heterocyclyl groups (the phenyl groups and the 5 to 6-membered aromatic heterocyclyl groups are unsubstituted or substituted with a substituent selected from the group consisting of a halogen atom, a cyano group, a C₁₋₃ alkyl group and a C₁₋₃ haloalkyl group))), and R^(2b) is a hydrogen atom, a C₁₋₆ alkyl group, or a C₂₋₆ alkenyl group (the C₁₋₆ alkyl group and the C₂₋₆ alkenyl group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(5b)), a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 14. The compound according to claim 2, wherein L^(1b) is a single bond or a C₁₋₃ alkylene group, L^(2b) is a single bond or a C₁₋₃ alkylene group (the C₁₋₃ alkylene group is unsubstituted or substituted with a cyano group or a C₁₋₃ haloalkyl group), the ring B^(b) is a C₃₋₁₁ cycloalkane, a C₃₋₁₁ cycloalkene, a 3 to 11-membered non-aromatic heterocycle, benzene or a 5 to 6-membered aromatic heterocycle, n^(b) is 0 or 1, R^(3b) is a hydroxy group, an amino group, a carbamoyl group, a halogen atom, a cyano group, a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group, a C₃₋₆ cycloalkyl group, a C₁₋₃ alkoxy group, a C₁₋₃ haloalkoxy group or a C₁₋₃ alkylsulfonyl group, L^(3b) is represented by any of the following formulae (VI^(b)-1) to (VI^(b)-11):

(wherein E^(1b) is an oxygen atom, each of R^(12b) and R^(13b) is independently a hydrogen atom, a C₁₋₆ alkyl group or a C₁₋₆ haloalkyl group), and R^(2b) is a hydrogen atom, a C₁₋₆ alkyl group, or a C₂₋₆ alkenyl group (the C₁₋₆ alkyl group and the C₂₋₆ alkenyl group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(5b)), a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 15. The compound according to claim 13, wherein the ring B^(b) is a C₃₋₁₁ cycloalkane or a 4 to 7-membered non-aromatic heterocycle, L^(3b) is represented by any of the following formulae (XIX^(b)-1) to (XIX^(b)-7):

(wherein E^(1b) is an oxygen atom, and R^(12b) is a hydrogen atom, a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is unsubstituted or substituted with one or more identical or different substituents independently selected from the group consisting of cyano groups, hydroxy groups, C₁₋₃ alkoxy groups, C₃₋₆ cycloalkyl groups and phenyl groups) or a C₁₋₆ haloalkyl group), and R^(2b) is a hydrogen atom, a C₁₋₆ alkyl group, or a C₂₋₆ alkenyl group (the C₁₋₆ alkyl group and the C₂₋₆ alkenyl group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(5b)), a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 16. The compound according to claim 8, wherein L^(2b) is a single bond or a C₁₋₃ alkylene group, a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 17. The compound according to claim 4, wherein X^(b) is a nitrogen atom or CR^(15b) (wherein R^(15b) is a hydrogen atom), and Y^(b) is CR^(16b) (wherein R^(16b) is a hydrogen atom), a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 18. The compound according to claim 2, wherein the ring B^(b) is cyclohexane or piperidine, a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 19. The compound according to claim 1, wherein X^(b) is a nitrogen atom or CR^(15b) (wherein R^(15b) is a hydrogen atom or a halogen atom), Y^(b) is CR^(16b)(wherein R^(16b) is a hydrogen atom), R^(1b) is a hydrogen atom, the ring A^(b) is represented by any of the following formulae (XVIII^(b)-1) to (XVIII^(b)-8):

(wherein each of E^(2b) and E^(3b) is independently an oxygen atom or a sulfur atom, each of R^(4b), R^(5b), R^(6b), R^(8b) and R^(9b) is independently a hydrogen atom, a halogen atom or a C₁₋₃ alkyl group, and R^(10b) is a hydrogen atom, a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(3b)), a C₃₋₁₁ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclyl group, a C₆₋₁₄ aryl group or a 5 to 10-membered aromatic heterocyclyl group (the C₃₋₁₁ cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclyl group, the C₆₋₁₄ aryl group and the 5 to 10-membered aromatic heterocyclyl group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(1b))), the ring B^(b) is a C₃₋₁₁ cycloalkane, a 3 to 11-membered non-aromatic heterocycle, a C₆₋₁₄ aromatic carbocycle or a 5 to 10-membered aromatic heterocycle, L^(1b) is single bond or a C₁₋₃ alkylene group, L^(2b) is a single bond, a C₁₋₆ alkylene group or a C₂₋₆ alkenylene group (the C₁₋₆ alkylene group and the C₂₋₆ alkenylene group are unsubstituted or substituted with one or more identical or different substituents independently selected from the group consisting of halogen atoms, hydroxy groups, amino groups, cyano groups and nitro groups), n^(b) is 0 or 1, R^(3b) is a hydroxy group, an amino group, a carboxy group, a carbamoyl group, a tetrazolyl group, a halogen atom, a cyano group, a nitro group, a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group, a C₃₋₆ cycloalkyl group, a C₁₋₃ alkoxy group, a C₁₋₃ haloalkoxy group or a C₁₋₃ alkylsulfonyl group, L^(3b) is a single bond or represented by any of the following formulae (XXII^(b)-1) to (XXII^(b)-15):

(wherein E^(1b) is an oxygen atom or a sulfur atom, and each of R^(12b) and R^(13b) is independently a hydrogen atom, a C₁₋₆ alkyl group or a C₁₋₆ haloalkyl group (the C₁₋₆ alkyl group and the C₁₋₆ haloalkyl group are unsubstituted or substituted with one or more identical or different substituents independently selected from the group consisting of halogen atoms, cyano groups, hydroxy groups, C₁₋₆ alkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆ alkylsulfonyl groups, C₃₋₆ cycloalkyl groups, 4 to 7-membered non-aromatic heterocyclyl groups, phenyl groups and 5 to 6-membered aromatic heterocyclyl groups (the phenyl groups and 5 to 6-membered aromatic heterocyclyl groups are unsubstituted or substituted with a substituent selected from the group consisting of a halogen atom, a cyano group, a C₁₋₃ alkyl group and a C₁₋₃ haloalkyl group))), when L^(3b) is a single bond, R^(2b) is a hydrogen atom, a halogen atom, a C₃₋₁₁ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclyl group, a phenyl group, a naphthyl group, a 5 to 10-membered aromatic heterocyclyl group, a 8 to 11-membered partially saturated aromatic cyclic group or a 8 to 11-membered aromatic ring-condensed alicyclic hydrocarbon group (the C₃₋₁₁ cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclyl group, the phenyl group, the naphthyl group, the 5 to 10-membered aromatic heterocyclyl group, the 8 to 11-membered partially saturated aromatic cyclic group and the 8 to 11-membered aromatic ring-condensed alicyclic hydrocarbon group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(4b) and the substituent set V^(9b)), when L^(3b) is not a single bond, R^(2b) is a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group (the C₁₋₆ alkyl group and the C₂₋₆ alkenyl group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(6b) and the substituent set V^(9b)), a C₃₋₁₁ cycloalkyl group, a 3 to 11-membered non-aromatic heterocyclyl group, a C₆₋₁₄ aryl group, a 5 to 10-membered aromatic heterocyclyl group, a 8 to 11-membered partially saturated aromatic cyclic group or a 8 to 11-membered aromatic ring-condensed alicyclic hydrocarbon group (the C₃₋₁₁ cycloalkyl group, the 3 to 11-membered non-aromatic heterocyclyl group, the C₆₋₁₄ aryl group, the 5 to 10-membered aromatic heterocyclyl group, the 8 to 11-membered partially saturated aromatic cyclic group or the 8 to 11-membered aromatic ring-condensed alicyclic hydrocarbon group are unsubstituted or substituted with one or more identical or different substituents independently selected from the substituent set V^(4b) and the substituent set V^(9b)), a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 20. The compound according to claim 1, wherein the ring A^(b) is represented by any of the following formulae (XXI^(b)-1) to (XXI^(b)-4):

(wherein each of E^(2b) and E^(3b) is independently an oxygen atom or a sulfur atom, R^(4b), R^(5b), R^(8b) and R^(9b) are hydrogen atoms, R^(6b) is a hydrogen atom, a halogen atom or a C₁₋₃ alkyl group, and R^(10b) is a hydrogen atom, a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is unsubstituted or substituted with one or two identical or different substituents independently selected from the group consisting of cyano groups, hydroxy groups, C₁₋₃ alkoxy groups, C₁₋₃ alkylthio groups, mono-C₁₋₃ alkylamino groups, di-C₁₋₃ alkylamino groups, mono-C₁₋₃ alkylaminocarbonyl groups, di-C₁₋₃ alkylaminocarbonyl groups, C₃₋₆ cycloalkyl groups, 4 to 7-membered non-aromatic heterocyclyl groups, phenyl groups and 5 to 6-membered aromatic heterocyclyl groups (the phenyl groups and the 5 to 6-membered aromatic heterocyclyl groups are unsubstituted or substituted with one or two identical or different substituents independently selected from the group consisting of halogen atoms, C₁₋₃ alkyl groups and C₁₋₃ haloalkyl groups)), a C₁₋₆ haloalkyl group, a C₃₋₆ cycloalkyl group or a 4 to 7-membered non-aromatic heterocyclyl group), a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 21. The compound according to claim 1, wherein the ring A^(b) is represented by the following formulae (XXIX^(b)-1) or (XXIX^(b)-2):

(wherein E^(2b) and E^(3b) are oxygen atoms, R^(6b) is a hydrogen atom, a halogen atom or a C₁₋₃ alkyl group, R^(8b) is a hydrogen atom, and R^(10b) is a hydrogen atom, a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is unsubstituted or substituted with one or two identical or different substituents independently selected from the group consisting of cyano groups, hydroxy groups, C₁₋₃ alkoxy groups, C₁₋₃ alkylthio groups, di-C₁₋₃ alkylamino groups, C₃₋₆ cycloalkyl groups and 4 to 7-membered non-aromatic heterocyclyl groups), a C₁₋₆ haloalkyl group, a C₃₋₆ cycloalkyl group or a 4 to 7-membered non-aromatic heterocyclyl group, a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 22. The compound according to claim 1, wherein L^(1b) is a single bond, L^(2b) is a single bond, a C₁₋₆ alkylene group, a C₂₋₆ alkenylene group or a C₁₋₆ haloalkylene group (the C₁₋₆ alkylene group, the C₂₋₆ alkenylene group and the C₁₋₆ haloalkylene group are unsubstituted or substituted with a hydroxy group or a cyano group), the ring B^(b) is a C₃₋₁₁ cycloalkane or a 4 to 7-membered non-aromatic heterocycle, n^(b) is 0 or 1, and R^(3b) is a hydroxy group, a C₁₋₃ alkyl group or a C₁₋₃ alkoxy group, a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 23. The compound according to claim 1, wherein L^(3b) is represented by any of the following formulae (XIX^(b)-1) to (XIX^(b)-7):

(wherein E^(1b) is an oxygen atom, and R^(12b) is a hydrogen atom or a C₁₋₆ alkyl group (the C₁₋₆ alkyl group is unsubstituted or substituted with one or more identical or different substituents independently selected from the group consisting of halogen atoms, cyano groups, hydroxy groups, C₁₋₃ allkoxy groups, C₃₋₆ cycloalkyl groups, 4 to 7-membered non-aromatic heterocyclyl groups, phenyl groups and 5 to 6-membered aromatic heterocyclyl groups)), and R^(2b) is a hydrogen atom, a C₁₋₆ alkyl group, a C₁₋₆ haloalkyl group (the C₁₋₆ alkyl group and the C₁₋₆ haloalkyl group are unsubstituted or substituted with one or two identical or different substituents independently selected from the group consisting of cyano groups, hydroxy groups, C₁₋₆ alkoxy groups, C₁₋₆ alkylthio groups, C₁₋₆ alkylsulfonyl groups, C₃₋₆ cycloalkyl groups, 4 to 7-membered non-aromatic heterocyclyl groups, phenyl groups and 5 to 6-membered aromatic heterocyclyl groups (the C₃₋₆ cycloalkyl groups, the 4 to 7-membered non-aromatic heterocyclyl groups, the phenyl groups and the 5 to 6-membered aromatic heterocyclyl groups are unsubstituted or substituted with one, two or three identical or different substituents independently selected from the group consisting of the substituent set V^(2b), mono-C₁₋₆ alkylaminosulfonyl groups and di-C₁₋₆ alkylaminosulfonyl groups)), a C₃₋₆ cycloalkyl group, a 4 to 7-membered non-aromatic heterocyclyl group, a phenyl group, a 5 to 6-membered aromatic heterocyclyl group or a 8 to 11-membered partially saturated aromatic cyclic group (the C₃₋₆ cycloalkyl group, the 4 to 7-membered non-aromatic heterocyclyl group, the phenyl group, the 5 to 6-membered aromatic heterocyclyl group and the 8 to 11-membered partially saturated aromatic cyclic group are unsubstituted or substituted with one, two or three identical or different substituents independently selected from the group consisting of the substituent set V^(2b), mono-C₁₋₆ alkylaminosulfonyl groups and di-C₁₋₆ alkylaminosulfonyl groups), a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 24. The compound according to claim 23, wherein L^(3b) is represented by the formula (XXXII^(b)):

(wherein R^(12b) is a hydrogen atom, a C₁₋₃ alkyl group (the C₁₋₃ alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of a cyano group, a hydroxy group, a C₁₋₃ allkoxy group, a C₃₋₆ cycloalkyl group and a phenyl group) or a C₁₋₃ haloalkyl group), and R^(2b) is a hydrogen atom, a C₁₋₃ alkyl group, a C₁₋₃ haloalkyl group (the C₁₋₃ alkyl group and the C₁₋₃ haloalkyl group are unsubstituted or substituted with one or two identical or different substituent selected from the group consisting of hydroxy groups, cyano groups, C₁₋₃ alkoxy groups, C₃₋₆ cycloalkyl groups (the C₃₋₆ cycloalkyl groups are unsubstituted or substituted with a hydroxy groups), 4 to 7-membered non-aromatic heterocyclyl groups, phenyl groups and 5 to 6-membered aromatic heterocyclyl groups), a C₃₋₆ cycloalkyl group or a 4 to 7-membered non-aromatic heterocyclyl group (the C₃₋₆ cycloalkyl group and the 4 to 7-membered non-aromatic heterocyclyl group are unsubstituted or substituted with one or two identical or different substituents independently selected from the group consisting of C₁₋₃ alkyl groups, C₁₋₃ haloalkyl groups and C₁₋₆ alkoxycarbonyl groups), a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 25. The compound according to claim 1, wherein L^(2b) is a single bond or a C₁₋₃ alkylene group, and the ring B^(b) is cyclohexane or piperidine, a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 26. The compound according to claim 1, wherein n^(b) is 0 or 1, and R^(3b) is a C₁₋₃ alkyl group, a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof.
 27. A JAK inhibitor containing the compound as defined in claim 1, a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof, as an active ingredient.
 28. A preventive, therapeutic or improving agent for diseases against which inhibition of JAK is effective, which contains the JAK inhibitor as defined in claim
 27. 29. A therapeutic agent for articular rheumatism, which contains the JAK inhibitor as defined in claim
 27. 30. A medicament containing the compound as defined in claim 1, a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof, as an active ingredient. 